In-Hospital Initiation of Sacubitril/Valsartan: A New PARADIGM for Acute Decompensated Heart Failure? No abstract available
The incidence and prevalence of heart failure (HF) is not decreasing, and its morbidity remains extremely high1,2 with future projections predicting further increases in incidence and costs over the next 20 years.1
Neurohormonal pathways [eg, renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system] have long been recognized as playing an important role in HF pathophysiology.3 More recently, the role of counter-regulatory systems that may work to delay disease progression has been recognized.4 The best characterized mediators of these systems are the natriuretic peptides, for example, atrial, brain, and C-type natriuretic peptide.5 Plasma levels of B-type natriuretic peptide (BNP) are increased in patients with left ventricular dysfunction. Therefore, BNP is a useful and established biomarker for aiding the diagnosis of HF. The increase in natriuretic peptides is likely a conserved compensatory mechanism to combat the overactivation of both RAAS and sympathetic nervous system, and the correlation between elevations of these peptides and disease progression is sometimes referred to as the “natriuretic peptide paradox.”6 Both the neurohormonal and natriuretic systems are notably activated in patients with acutely decompensated HF (ADHF).
Therapeutic strategies that mimic or manipulate natriuretic peptide concentrations have been developed and clinically tested. Inhibition of neprilysin, an enzyme that degrades natriuretic peptides, is increasingly being studied in expanded cardiac populations.7 When the inhibition of RAAS using an angiotensin II receptor blocker and neprilysin was combined, the effects were found to be superior to those of either approach alone in experimental studies.8,9 The first Food and Drug Administration (FDA)–approved combination of a neprilysin inhibitor and angiotensin II receptor blocker was sacubitril/valsartan following the results of the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial. PARADIGM-HF found a 20% reduction in major cardiac events (hazard ratio 0.80, 95% confidence interval 0.73–0.87, P < 0.001) for the treatment versus enalapril over 3.4 years of follow-up (Figure 1).10 The population studied in PARADIGM-HF, however, was patients with stable HF therefore leaving the benefit and safety in ADHF unknown (Figure 1).
Relative to the therapeutic strategies for chronic HF, few interventions have been tested in ADHF11 and many interventions have failed. The RELAX-AHF (RELAX in Acute Heart Failure) trial with serelaxin, a recombinant version of the vasodilatory human relaxin hormone that becomes elevated during pregnancy, failed to show a significant reduction in cardiovascular death or readmission for HF,12 despite encouraging results of the phase II pre–RELAX-AHF trial. Similarly, in the TRUE-AHF (Trial of Ularitide Efficacy and Safety in Acute Heart Failure) trial, ularitide, a hormone inducing natriuresis, did not reduce the long-term risk of cardiovascular death.13 Nesiritide, a recombinant BNP, was approved by FDA for ADHF in 2001 after showing benefit in surrogate hemodynamic endpoints of HF. However, in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure) trial, nesiritide failed to show improvement for the composite endpoint of death and rehospitalization for HF (HHF) after a median of 41 hours of treatment.14 In all of these examples, short-term infusions of the aforementioned treatments in ADHF failed to translate into clinical outcome benefits, consistent with the historical futility of short-term ADHF interventions to influence long-term cardiovascular outcomes.
In contrast with this previous studies, the PIONEER-HF (Comparison of Sacubitril–Valsartan vs. Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute HF Episode) was a randomized (stratified by age at the time enrollment), double-blind, double-dummy, multicenter clinical trial that evaluated initiation—and outpatient continuation—of sacubitril/valsartan versus enalapril in 881 patients who were hospitalized for ADHF.15 The primary efficacy outcome of change in the N-terminal pro–B-type natriuretic peptide (NT-proBNP), a surrogate biomarker not elevated as a result of neprilysin inhibition, over the 8-week follow-up period was successfully reached (−46.7% vs. −25.3%, P < 0.001) (Figure 1). Key safety outcomes did not see any significant difference between groups. Prespecified exploratory analyses of clinical outcomes showed a 44% reduction in HHF for those treated with sacubitril/valsartan as compared to enalapril. For the studied population, this reduction is likely to be of importance given the natural history of the disease where a reduction in long-term survival is observed with each additional HHF.16
PIONEER-HF trial also found in-hospital initiation of sacubitril/valsartan in ADHF patients to be safe for patients once maintained on stable diuretic doses and not in the “hyperacute” phase (patients were enrolled no less than 24 hours after their initial presentation to the hospital). Although the early initiation of vasoactive drugs has been demonstrated to improve in-hospital mortality in patients hospitalized for ADHF,17 most of the oft-reported drugs tested for ADHF failed to show long-term benefits while initiated exactly during early recompensation differently from sacubitril/valsartan started following the stabilization of patients, as underlined by the inclusion criteria.
More than one-third of patients enrolled were black or African American, and no significant increase in the risk for angioedema was observed. The event rate of symptomatic hypotension was not different between treatment groups, which provides some reassurance against concerns for hypotension with in-patient initiation. The results may also confirm post hoc observations for associations of NT-proBNP levels and outcomes in PARADIGM-HF.18
Some limitations need to be acknowledged. First of all, because the PIONEER-HF trial pointed to evaluate the safety and efficacy of sacubitril/valsartan in patients with ADHF, it is quite surprising that the primary outcome was the change in the NT-proBNP concentrations, which, however, was significantly higher compared with enalapril but already seen in a subanalysis of the PARADIGM-HF.18 Second, key safety outcomes were reached showing that sacubitril/valsartan was safe, but most of these events showed wide confidence intervals, especially hyperkalemia (84%) and symptomatic hypotension (64%), suggesting, however, a strict surveillance for these patients.
In conclusion, sacubitril/valsartan initiated early in patients with ADHF was safe and effective in reducing HF outcomes within 8 weeks of follow-up. Whether this benefit is merely an extension of the benefits observed among patients with chronic HF with reduced ejection fraction (in the PARADIGM-HF study) or represents a distinct profile of benefits among ADHF patients remains unclear. In either case, however, the benefit of neprilysin inhibition presents a new paradigm for neurohormonal blockade in ADHF and defines a new standard of care. The pathophysiology and treatment of ADHF remains, however, complex, and additional studies are warranted to explore other mechanisms potentially involved in disease progression and acute decompensation of HF. Novel therapeutic targets may include the contractile function in the cardiomyocyte (myosin activators19), the vasculatures (adenosine20), the kidneys (sodium-dependent glucose cotransporter–2 inhibition21), the inflammatory response (interleukin-122), and others. Finally, considering that the prognosis of chronic HF is known to improve when other drugs, such as β-blockers23,24 and angiotensin-converting enzyme inhibitors,25 are not discontinued or early restarted during hospitalization in the need of withdrawal, it might be worth evaluating whether the discontinuation of sacubitril/valsartan is necessary or counterproductive in those ADHF patients already on the drug.
REFERENCES
1. Benjamin EJ, Muntner P, Alonso A, et al; American Heart Association Council on E, Prevention Statistics C, Stroke Statistics S. Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation. 2019;139:e56–e528.
2. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–2200.
3. Francis GS, Goldsmith SR, Levine TB, et al. The neurohumoral axis in congestive heart failure. Ann Intern Med. 1984;101:370–377.
4. Oatmen KE, Zile MR, Burnett JC Jr, et al. Bioactive signaling in next-generation pharmacotherapies for heart failure: a review. JAMA Cardiol. 2018. doi: [epub ahead of print].
5. Potter LR, Yoder AR, Flora DR, et al. Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications. Handb Exp Pharmacol. 2009:341–366.
6. Goetze JP, Kastrup J, Rehfeld JF. The paradox of increased natriuretic hormones in congestive heart failure patients: does the endocrine heart also fail in heart failure? Eur Heart J. 2003;24:1471–1472.
7. Owens AT, Brozena S, Jessup M. Neprilysin inhibitors: emerging therapy for heart failure. Annu Rev Med. 2017;68:41–49.
8. Rademaker MT, Charles CJ, Espiner EA, et al. Combined neutral endopeptidase and angiotensin-converting enzyme inhibition in heart failure: role of natriuretic peptides and angiotensin II. J Cardiovasc Pharmacol. 1998;31:116–125.
9. Trippodo NC, Fox M, Monticello TM, et al. Vasopeptidase inhibition with omapatrilat improves cardiac geometry and survival in cardiomyopathic hamsters more than does ACE inhibition with captopril. J Cardiovasc Pharmacol. 1999;34:782–790.
10. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004.
11. Cannon JA, McKean AR, Jhund PS, et al. What can we learn from RELAX-AHF compared to previous AHF trials and what does the future hold? Open Heart. 2015;2:e000283.
12. Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet. 2013;381:29–39.
13. Packer M, O'Connor C, McMurray JJV, et al. Effect of ularitide on cardiovascular mortality in acute heart failure. N Engl J Med. 2017;376:1956–1964.
14. O'Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med. 2011;365:32–43.
15. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med. 2019;380:539–548.
16. Abbate A, Arena R, Abouzaki N, et al. Heart failure with preserved ejection fraction: refocusing on diastole. Int J Cardiol. 2015;179:430–440.
17. Peacock WF, Emerman C, Costanzo MR, et al. Early vasoactive drugs improve heart failure outcomes. Congest Heart Fail. 2009;15:256–264.
18. Zile MR, Claggett BL, Prescott MF, et al. Prognostic implications of changes in N-terminal pro-B-type natriuretic peptide in patients with heart failure. J Am Coll Cardiol. 2016;68:2425–2436.
19. Moin DS, Sackheim J, Hamo CE, et al. Cardiac myosin activators in systolic heart failure: more friend than foe? Curr Cardiol Rep. 2016;18:100.
20. Voors AA, Shah SJ, Bax JJ, et al. Rationale and design of the phase 2b clinical trials to study the effects of the partial adenosine A1-receptor agonist neladenoson bialanate in patients with chronic heart failure with reduced (PANTHEON) and preserved (PANACHE) ejection fraction. Eur J Heart Fail. 2018;20:1601–1610.
21. Bonaventura A, Carbone S, Dixon DL, et al. Pharmacologic strategies to reduce cardiovascular disease in type 2 diabetes mellitus: focus on SGLT-2 inhibitors and GLP-1 receptor agonists. J Intern Med. 2019. doi: [epub ahead of print].
22. Van Tassell BW, Canada J, Carbone S, et al. Interleukin-1 blockade in recently decompensated systolic heart failure: results from REDHART (recently decompensated heart failure anakinra response trial). Circ Heart Fail. 2017;10:e004373.
23. Prins KW, Neill JM, Tyler JO, et al. Effects of beta-blocker withdrawal in acute decompensated heart failure: a systematic review and meta-analysis. JACC Heart Fail. 2015;3:647–653.
24. Jondeau G, Milleron O. Beta-blockers in acute heart failure: do they cause harm? JACC. Heart Fail. 2015;3:654–656.
25. Gilstrap LG, Fonarow GC, Desai AS, et al. Initiation, continuation, or withdrawal of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and outcomes in patients hospitalized with heart failure with reduced ejection fraction. J Am Heart Assoc. 2017;6:e004675.
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Bioactive Lipids as Mediators of the Beneficial Actions of Statins No abstract available
Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is known to be of significant benefit in the treatment of hyperlipidemias. In addition, statins have the ability to attenuate matrix metalloprotease activity, reduce inflammatory response, restore antioxidant defenses, and reduce endoplasmic reticulum stress.1,2 Some of these beneficial actions of statins seem to be brought about by their ability to upregulate Nrf2 expression and stimulate Nrf2 nuclear translocation, induce antioxidant enzymes (HO-1, NQO1, and GCLC), and modulate PI3K/Akt/ERK pathway.3,4 It was reported that simvastatin markedly suppressed PI3K/Akt/mTOR signaling by activating PTEN and by dephosphorylating Akt and S6RP (P = 0.033); it also inhibited MAPK/ERK pathway by dephosphorylating c-Raf and ERK1/2. These results suggest that statins may have cytoprotective action.
This is supported by the observation that doxorubicin can cause glomerulosclerosis by enhancing the expression of NF-kB, IL-1β, and TGF-β inflammation and simvastatin suppressed these expressions and, thus, seems to bring about its nephroprotective action.5 It is noteworthy that simvastatin directly inhibits ATP-binding cassette transporters such as ABCB1 (P-glycoprotein), an important mechanism of multidrug resistance in cancer therapy, and, thus, brings about its (simvastatin) anticancer action and also potentiated (especially lovastatin) apoptosis of cancer cells induced by conventional anticancer drugs.6–8 In this context, it is interesting to note that atorvastatin can protect cardiac tissue from the cytotoxic action of doxorubicin.9 These interesting results open a new window of opportunity to protect cardiac toxicity induced by doxorubicin. But, obviously more studies are needed to extrapolate these results to humans. Most important of all is to find out whether all statins have similar cardioprotective action against doxorubicin.
Based on these results, it remains to be studied whether statins possess differential action on normal and tumor cells, wherein normal cells (such as cardiac and renal) are protected from the cytotoxic action of doxorubicin and simultaneously are able to show anticancer action and potentiate the tumoricidal action of anticancer drugs. Such an action of statins, if proved to be true, it would certainly be a boon to cancer patients and enhance the armamentarium of physicians in their fight against cancer. It is also not certain whether such differential action of statins on normal and tumor cells is possessed by all statins or is restricted to certain statins only.
Previously, I proposed that statins may bring about some of their beneficial actions by modulating the metabolism of essential fatty acids (EFAs).10 This proposal has since been supported by several other studies.11–15 It was reported that statins enhance dietary linoleic acid (LA, 18:2 n-6) and possibly that of α-linolenic acid (ALA, 18:3 n-3) metabolism and enhance the formation of their long-chain metabolites such as γ-linolenic acid (GLA, 18:3 n-6), dihomo-GLA (DGLA, 20:3 n-6), arachidonic acid (from LA), eicosapentaenoic acid (EPA, 20:5 n-3), and docosahexaenoic acid (DHA, 22:6 n-3) (from ALA). Statins seem to enhance specifically the formation of AA by augmenting the activity of [INCREMENT]5desaturase compared with all other fatty acids14,16–21 and its (AA) conversion to prostacyclin and lipoxin A4 (LXA4) and increase the production of nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) that are potent platelet antiaggregators and vasodilators.17,22–26 All these polyunsaturated fatty acids (PUFAs such as GLA, DGLA, AA, EPA, and DHA) reduce plasma cholesterol and triglycerides, inhibit the action of HMG-CoA reductase activity, possess anti-inflammatory action by virtue of their ability to suppress the production of IL-6 and TNF-α, prevent platelet aggregation, and cause vasodilatation either directly or by forming precursors to vasodilator eicosanoids and enhancing the formation of NO, CO, H2S, and LXA4 (from AA) and possibly, augmenting the formation of resolvins, protectins, and maresins (from EPA and DHA).17,22–27 Some of these actions are somewhat similar to the actions of statins implying that statins bring about some, if not all, of their beneficial actions by modulating EFA metabolism.10 If this is true, it suggests that even the cardioprotective action of statins could be related to their influence on EFA metabolism (Fig. 1).
Our previous studies revealed that GLA, DGLA, AA, EPA, and DHA may have selective tumoricidal action with no adverse actions on normal cells in vitro and in vivo.28–32 In addition, it was noted that these fatty acids are able to prevent cytotoxic action of various chemicals and radiation on normal cells.33–35 Furthermore, PUFAs enhance the tumoricidal action of various conventional anticancer drugs on cancer cells.36–38 This selective yet differential action of PUFAs on normal and tumor cells is reminiscent of the cardioprotective action of statins against doxorubicin-induced toxicity and the ability of statins to enhance the tumoricidal action of anticancer therapeutics.3,4,7,8 These results imply that PUFAs and statins may have a common mechanism of action in bringing about their cytoprotective action on normal and chemosensitizing action on tumor cells in addition to their action on Hsp70, p-Akt, p-ERK, and p-JNK signaling (Fig. 2).3,4,10,39–45 Such a common pathway could be their ability to enhance LXA4 formation (statins increase LXA4 formation, whereas AA forms the precursor of LXA4). Our recent studies revealed that LXA4 protects normal cells against chemical-induced toxicity yet is able to suppress tumor cell proliferation.33 If this is true, it implies that PUFAs are needed for various beneficial actions of statins, and PUFA deficiency would hinder their actions. Based on these data, it can be suggested that a combination of PUFAs and statins will be highly beneficial in the management of hyperlipidemias and prevention of cardiovascular disease.46,47
This proposal is supported by the recently concluded multicenter, randomized, double-blind, placebo-controlled trial involving 8179 patients who had established cardiovascular disease or with diabetes and other risk factors, who had been receiving statins, and who had a fasting triglyceride level of 135–499 mg per deciliter and a low-density lipoprotein cholesterol level of 41–100 mg per deciliter when were administered 2 gm of icosapent ethyl (which is a highly purified and stable EPA ethyl ester) twice a day showed significantly lower risk of ischemic events, including cardiovascular death compared with those who received the placebo.48,49 Paradoxically, in another study that conducted a randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (at a dose of 2000 IU per day) and marine n-3 fatty acids (at a dose of 1 g per day that contained 460 mg of EPA and 380 mg of DHA) in the primary prevention of cardiovascular disease and cancer among men 50 years of age or older and women 55 years of age or older did not show any reduction in major cardiovascular events or cancer compared with the placebo.50,51
These apparently paradoxical results from 2 studies that used pure n-3 EPA in one and a combination of n-3 EPA and DHA plus vitamin D in the final outcome of the results are perplexing but not unexpected. It is noteworthy that in the icosapent ethyl (which is a highly purified and stable EPA ethyl ester) study,48,49 4 gm of the fatty acid was administered per day, whereas in the fish oil supplement study, only 1 gm of fish oil that contained 460 mg of EPA and 380 mg of DHA was used,50,51 which in terms of weight per weight dose was much less. This could have been responsible for the negative results with the fish oil supplement. The second reason could be the presence of other fatty acids in the fish oil capsule. It is well known that fish oil supplements contain significant amounts of saturated fatty acids and oxidized lipids in addition to their EPA/DHA content that may interfere with the biological activity of EPA/DHA.52 In addition, it is known that the beneficial actions of EPA/DHA are brought about to a large extent by their anti-inflammatory metabolites resolvins, protectins, and maresins.53,54 It is possible that the presence of significant amounts of saturated fatty acids and lipid peroxides in the fish oil capsules may have prevented the formation resolvins, protectins, and maresins from their precursors EPA/DHA that could explain the negative results seen with fish oil capsules. Hence, any future studies that are designed to study the beneficial actions of EPA/DHA need to consider these facts and should be performed with pure fatty acids that are devoid of any saturated and/or transfatty acids and lipid peroxides in their content. In this context, it will be interesting to study whether pure ethyl esters of EPA or DHA or a combination of ethyl esters of EPA and DHA and ethyl ester of AA will be as potent as that of icosapent ethyl (which is a highly purified and stable EPA ethyl ester) in preventing cardiovascular events, lowering plasma cholesterol, triglycerides, LDL, and enhancing HDL. In view of this, it is suggested that a high quality at least a single centered if not multicentered study in which plasma levels of various PUFAs (including AA, EPA, and DHA) and their anti-inflammatory metabolites lipoxins, resolvins, protectins, and maresins are measured both before and after the supplementation of statins, and PUFAs (AA/EPA/DHA or a combination there of) are studied to delineate their (statins ± PUFAs) possible beneficial actions in hyperlipidemias, cardiovascular diseases including hypertension and diabetes mellitus. Such a study would answer the potential relationship between statins and PUFAs metabolism and the role of PUFAs and their metabolites in hyperlipidemias and cardiovascular diseases.
Thus, it is evident from the preceding discussion that a combination of statins and PUFAs may have a significant benefit not only in the management of hyperlipidemias, prevention and management of cardiovascular diseases and cancer (with or without in combination with chemotherapeutic drugs) by virtue of their potent anti-inflammatory and immunomodulatory actions but also in other inflammatory conditions such as sepsis, lupus, inflammatory bowel disease, and nonalcoholic fatty liver disease.
REFERENCES
1. Yamada Y, Takeuchi S, Yoneda M, et al. Atorvastatin reduces cardiac and adipose tissue inflammation in rats with metabolic syndrome. Int J Cardiol. 2017;240:332–338.
2. Psarros C, Economou EK, Koutsilieris M, et al. Statins as pleiotropic modifiers of vascular oxidative stress and inflammation. J Crit Care Med (Targu Mures). 2015;1:43–54.
3. Jang HJ, Hong EM, Kim M, et al. Simvastatin induces heme oxygenase-1 via NF-E2-related factor 2 (Nrf2) activation through ERK and PI3K/Akt pathway in colon cancer. Oncotarget. 2016;7:46219–46229.
4. Wang T, Seah S, Loh X, et al. Simvastatin-induced breast cancer cell death and deactivation of PI3K/Akt and MAPK/ERK signalling are reversed by metabolic products of the mevalonate pathway. Oncotarget. 2016;7:2532–2544.
5. Zhang W, Li Q, Wang L, et al. Simvastatin ameliorates glomerulosclerosis in Adriamycin-induced-nephropathy rats. Pediatr Nephrol. 2008;23:2185–2194.
6. Atil B, Berger-Sieczkowski E, Bardy J, et al. In vitro and in vivo downregulation of the ATP binding cassette transporter B1 by the HMG-CoA reductase inhibitor simvastatin. Naunyn Schmiedebergs Arch Pharmacol. 2016;389:17–32.
7. Werner M, Sacher J, Hohenegger M. Mutual amplification of apoptosis by statin-induced mitochondrial stress and doxorubicin toxicity in human rhabdomyosarcoma cells. Br J Pharmacol. 2004;143:715–724.
8. Martirosyan A, Clendening JW, Goard CA, et al. Lovastatin induces apoptosis of ovarian cancer cells and synergizes with doxorubicin: potential therapeutic relevance. BMC Cancer. 2010;10:103.
9. Gao G, Jiang S, Ge L, et al. Atorvastatin improves doxorubicin-induced cardiac dysfunction by modulating Hsp70, Akt and MAPK signalling pathways. J Cardiovasc Pharmacol. 2019;73:223–231.
10. Das UN. Essential fatty acids as possible mediators of the actions of statins. Prostaglandins Leukot Essent Fatty Acids. 2001;65:37–40.
11. Ishihara N, Suzuki S, Tanaka S, et al. Atorvastatin increases Fads1, Fads2 and Elovl5 gene expression via the geranylgeranyl pyrophosphate-dependent Rho kinase pathway in 3T3-L1 cells. Mol Med Rep. 2017;16:4756–4762.
12. Risé P, Ghezzi S, Levati MG, et al. Pharmacological modulation of fatty acid desaturation and of cholesterol biosynthesis in THP-1 cells. Lipids. 2003;38:841–846.
13. Risé P, Ghezzi S, Carissimi R, et al. Delta5 desaturase mRNA levels are increased by simvastatin via SREBP-1 at early stages, not via PPARalpha, in THP-1 cells. Eur J Pharmacol. 2007;571:97–105.
14. Georges B, Blond JP, Maniongui C, et al. Effect of simvastatin on desaturase activities in liver from lean and obese Zucker rats. Lipids. 1993;28:63–65.
15. Nakamura N, Hamazaki T, Jokaji H, et al. Effect of HMG-CoA reductase inhibitors on plasma polyunsaturated fatty acid concentrations in patients with hyperlipidemia. Int J Clin Lab Res. 1998;28:192–195.
16. Risé P, Pazzucconi F, Sirtori CR, et al. Statins enhance arachidonic acid synthesis in hypercholesterolemic patients. Nutr Metab Cardiovasc Dis. 2001;11:88–94.
17. Levine L. Statins stimulate arachidonic acid release and prostaglandin I2 production in rat liver cells. Lipids Health Dis. 2003;2:1.
18. Hrboticky N, Tang L, Zimmer B, et al. Lovastatin increases arachidonic acid levels and stimulates thromboxane synthesis in human liver and monocytic cell lines. J Clin Invest. 1994;93:195–203.
19. Risé P, Colombo C, Galli C. Effects of simvastatin on the metabolism of polyunsaturated fatty acids and on glycerolipid, cholesterol, and de novo lipid synthesis in THP-1 cells. J Lipid Res. 1997;38:1299–1307.
20. Risé P, Ghezzi S, Priori I, et al. Differential modulation by simvastatin of the metabolic pathways in the n-9, n-6 and n-3 fatty acid series, in human monocytic and hepatocytic cell lines. Biochem Pharmacol. 2005;69:1095–1100.
21. Harris JI, Hibbeln JR, Mackey RH, et al. Statin treatment alters serum n-3 and n-6 fatty acids in hypercholesterolemic patients. Prostaglandins Leukot Essent Fatty Acids. 2004;71:263–269.
22. Chou TC, Lin YF, Wu WC, et al. Enhanced nitric oxide and cyclic GMP formation plays a role in the anti-platelet activity of simvastatin. Br J Pharmacol. 2008;153:1281–1287.
23. Levy BD. Myocardial 15-epi-lipoxin A4 generation provides a new mechanism for the immunomodulatory effects of statins and thiazolidinediones. Circulation. 2006;114:873–875.
24. Birnbaum Y, Ye Y, Lin Y, et al. Augmentation of myocardial production of 15-epi-lipoxin-a4 by pioglitazone and atorvastatin in the rat. Circulation. 2006;114:929–935.
25. Planagumà A, Pfeffer MA, Rubin G, et al. Lovastatin decreases acute mucosal inflammation via 15-epi-lipoxin A4. Mucosal Immunol. 2010;3:270–279.
26. Das UN. Essential fatty acids and their metabolites could function as endogenous HMG-CoA reductase and ACE enzyme inhibitors, anti-arrhythmic, anti-hypertensive, anti-atherosclerotic, anti-inflammatory, cytoprotective, and cardioprotective molecules. Lipids Health Dis. 2008;7:37.
27. Bełtowski J, Jamroz-Wiśniewska A. Modulation of h(2)s metabolism by statins: a new aspect of cardiovascular pharmacology. Antioxid Redox Signal. 2012;17:81–94.
28. Madhavi N, Das UN. Effect of n-6 and n-3 fatty acids on the survival of vincristine sensitive and resistant human cervical carcinoma cells in vitro. Cancer Lett. 1994;84:31–41.
29. Begin ME, Ells G, Das UN, et al. Differential killing of human carcinoma cells supplemented with n-3 and n-6 polyunsaturated fatty acids. J Natl Cancer Inst. 1986;77:1053–1062.
30. Das UN. Tumoricidal action of cis-unsaturated fatty acids and its relationship to free radicals and lipid peroxidation. Cancer Lett. 1991;56:235–243.
31. Ramesh G, Das UN. Effect of dietary fat on diethylnitrosamine induced hepatocarcinogenesis in Wistar rats. Cancer Lett. 1995;95:237–245.
32. Das UN, Prasad VSSV, Reddy DR. Local application of gamma-linolenic acid in the treatment of human gliomas. Cancer Lett. 1995;94:147–155.
33. Sailaja P, Mani AM, Naveen KVG, et al. Effect of polyunsaturated fatty acids and their metabolites on bleomycin-induced cytotoxic action on human neuroblastoma cells in vitro. PLoS One. 2014;9:e114766.
34. Naveen KVG, Naidu VGM, Das UN. Arachidonic acid and lipoxin A4 attenuate alloxan-induced cytotoxicity to RIN5F cells in vitro and type 1 diabetes mellitus in vivo. Biofactors. 2017;43:251–271.
35. Naveen KVG, Naidu VGM, Das UN. Arachidonic acid and lipoxin A4 attenuate streptozotocin-induced cytotoxicity to RIN5F cells in vitro and type 1 and type 2 diabetes mellitus in vivo. Nutrition. 2017;35:61–80.
36. Sangeetha PS, Das UN. Docosahexaenoic acid and eicosapentaenoic acid potentiate the cytotoxicity of anti-cancer drugs on human cervical carcinoma (HeLa) cells in vitro. Med Sci Res. 1993;21:457–459.
37. Das UN, Madhavi N, Padma M, et al. Can tumor cell drug-resistance be reversed by essential fatty acids and their metabolites? Prostaglandins Leukot Essent Fatty Acids. 1998;58:39–54.
38. Das UN, Madhavi N. Effect of polyunsaturated fatty acids on drug-sensitive and resistant tumor cells in vitro. Lipids Health Dis. 2011;10:159.
39. Oksala NK, Paimela H, Alhava E. Heat-shock preconditioning affects restitution of isolated Guinea pig gastric mucosa by an arachidonic acid and protein synthesis dependent mechanism. Scand J Gastroenterol. 2002;37:1366–1373.
40. Chauvin L, Goupille C, Blanc C, et al. Long chain n-3 polyunsaturated fatty acids increase the efficacy of docetaxel in mammary cancer cells by downregulating Akt and PKCε/δ-induced ERK pathways. Biochim Biophys Acta. 2016;1861:380–390.
41. Ampuero J, Romero-Gomez M. Prevention of hepatocellular carcinoma by correction of metabolic abnormalities: role of statins and metformin. World J Hepatol. 2015;7:1105–1111.
42. Lim K, Han C, Dai Y, et al. Omega-3 polyunsaturated fatty acids inhibit hepatocellular carcinoma cell growth through blocking beta-catenin and cyclooxygenase-2. Mol Cancer Ther. 2009;8:3046–3055.
43. Vinciguerra M, Veyrat-Durebex C, Moukil MA, et al. PTEN down-regulation by unsaturated fatty acids triggers hepatic steatosis via an NF-kappaBp65/mTOR-dependent mechanism. Gastroenterology. 2008;134:268–280.
44. Neeli I, Yellaturu CR, Rao GN. Arachidonic acid activation of translation initiation signaling in vascular smooth muscle cells. Biochem Biophys Res Commun. 2003;309:755–761.
45. Lin CH, Lin HI, Chen ML, et al. Lovastatin protects neurite degeneration in LRRK2-G2019S parkinsonism through activating the Akt/Nrf pathway and inhibiting GSK3β activity. Hum Mol Genet. 2016;25:1965–1978.
46. Kim CH, Han KA, Yu J, et al. Efficacy and safety of adding omega-3 fatty acids in statin-treated patients with residual hypertriglyceridemia: ROMANTIC (Rosuvastatin-OMAcor iN residual hyperTrIglyCeridemia), a randomized, double-blind, and placebo-controlled trial. Clin Ther. 2018;40:83–94.
47. Benes LB, Bassi NS, Davidson MH. Omega-3 carboxylic acids monotherapy and combination with statins in the management of dyslipidemia. Vasc Health Risk Manag. 2016;12:481–490.
48. Bhatt DL, Steg PG, Miller M, et al. For the REDUCE-IT investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11–22.
49. Kastelein JJP, Stroes ESG. FISHing for the miracle of eicosapentaenoic acid. N Engl J Med. 2019;380:89–90.
50. Manson JE, Cook NR, Lee IM, et al; for the VITAL Research Group. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2019;380:23–32.
51. Keaney JF Jr, Rosen CJ. VITAL signs for dietary supplementation to prevent cancer and heart disease. N Engl J Med. 2019;380:91–93.
52. Mason RP, Sherratt SCR. Omega-3 fatty acid fish oil dietary supplements contain saturated fats and oxidized lipids that may interfere with their intended biological benefits. Biochem Biophys Res Commun. 2017;483:425–429.
53. Poorani R, Bhatt AN, Dwarakanath BS, et al. COX-2, aspirin and metabolism of arachidonic, eicosapentaenoic and docosahexaenoic acids and their physiological and clinical significance. Eur J Pharmacol. 2016;785:116–132.
54. Das UN. Lipoxins, resolvins, protectins, maresins and nitrolipids and their clinical implications with specific reference to diabetes mellitus and other diseases: Part II. Clin Lipidol. 2013;8:465–480.
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| Translational Implications for Targeting Ischemia-Induced Cardiac Inflammation by Ticagrelor: One Fits All or Dose Matters?
Ticagrelor is a selective and stable nonphosphate P2Y12 receptor antagonist, which can decrease platelet aggregation and prohibit thrombus formation through preventing the binding of adenosine diphosphate to the P2Y12 receptor.1 Based on positive findings from controlled clinical trials, PDY12 receptor blocker drugs, such as clopidogrel, prasugrel, and ticagrelor, are frequently applied combined with acetylsalicylic acid in today's clinical practice primarily with the aim to enhance platelet inhibition in patients presenting with acute coronary syndrome (ACS), undergoing percutaneous coronary intervention, or in preventive treatment of patients who are at high risk of thromboembolism, myocardial infarction, or stroke.2 Several clinical trials investigated the pros and cons of the several PDY12 receptor blockers available, sometimes in direct comparison. The randomized multicenter, double-blind PLATO trial including 18,624 patients with ACS showed that incidence of the primary end point after 12 months defined as composite of death from vascular causes, myocardial infarction, or stroke was significantly lower in the ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) as compared to the clopidogrel treatment group (300- to 600-mg loading dose, 75 mg daily thereafter).3 In a recently published clinical report, Li et al4 also demonstrated better results in STEMI patients with diabetes as risk factor regarding angina, stent thrombosis, and all-cause mortality at 1-month post-therapy when treated with ticagrelor (n = 100) as compared to clopidogrel-treated patients. Current guidelines of the European Society of Cardiology as well as the American College of Cardiology therefore specifically advice use of ticagrelor in a rising number of indications (Fig. 1).5,6 However, pathophysiological mechanisms of action—including positive as well as negative effects observed clinically—still remain, at least in part, obscure.
In a current study, Ye et al gave some further insights how ticagrelor, administered immediately before reperfusion by intraperitoneal injection, might protect against reperfusion injury: Both acute or chronic ticagrelor treatment (oral administration 300 mg/kg per day for 4 weeks starting 1 day after reperfusion), or their combination, improved myocardial function, attenuated fibrosis, and decreased collagen-III mRNA levels 4 weeks after ischemia/reperfusion. Ticagrelor also attenuated the increase in proinflammatory tumor necrosis factor-α, interleukin-1β, and interleukin-18 and increased anti-inflammatory 15-epi-lipoxin-A4 levels.7 Specific cardioprotective effects of ticagrelor administration including reduced necrotic injury and edema formation were also evidenced in a myocardial infarction swine model.8
In this issue of the Journal of Cardiovascular Pharmacology, Liu et al9 further extend our knowledge on previously predescribed anti-inflammatory effects when reporting that ticagrelor, applied through gavage post-LAD ligation, reduces ischemia-reperfusion injury through an NF-κB–dependent pathway in rats. Their present as well as previous findings10are generally in line with experimental results reported by other groups in the field, not only describing positive net effects on ischemia reperfusion injury—ultimately resulting in smaller infarct size—after administration of ticagrelor, but also specifically on inflammatory response. Positive effects on inflammatory markers have not only been evidenced in coronary artery disease, but recently also described in other pathologies such as pneumonia.11 The current study further extends our pathophysiological understanding in this regard, bringing more light into the complex mechanism of action of ticagrelor, suggesting a direct positive effect on inflammatory response in myocardial healing. However, while the anti-inflammatory mode of action described on the one hand apparently seems to add to the understanding of positive effects of ticagrelor, which have been described in addition to positive clopidogrel and also prasugrel effects, a closer look at the subject matter raises new questions, among others regarding ideal drug dosage.
Notably, the dual antiplatelet and anti-ischemic/inflammatory effects of ticagrelor without doubt seem to contribute to the generally favorable clinical results in patients with ACS. Nanhwan et al12 found that oral ticagrelor (0, 75, 150, or 300 mg/kg/d) administered for 7 days before 30-minute coronary artery ligation and 24-hour reperfusion reduced myocardial infarct size in a dose-dependent manner. However, ticagrelor was also found associated with a significantly higher rate of non–procedure-related major bleedings, including higher numbers of fatal intracranial bleeding as compared to clopidogrel.3 The clinical net benefit achieved by the use of P2Y12 receptor antagonists, either as monotherapy, dual, or even triple antiplatelet therapy, therefore is often obtained at the price of augmented bleedings, which are known to be strong predictors of adverse outcome in patients with ACS. In this context, it is important to note that—despite the clear superiority of ticagrelor over clopidogrel when looking at the primary end points in clinical practice only in recent trials—it was also revealed that clopidogrel was generally safer than ticagrelor with regard to bleedings.13 In this line, the PEGASUS-TIMI 54 trial randomly assigned 21,162 patients to 2 different doses of ticagrelor or placebo, revealing favorable net effects of 60-mg ticagrelor twice daily in direct comparison with 90-mg ticagrelor twice daily in patients who suffered from myocardial infarction 1–3 years before therapy. These findings led to the current guideline recommendations, supporting a reduced dosage of 60-mg ticagrelor twice daily for long-term use in stable coronary artery disease.14 Of note, in contrast to ticagrelor application, several clinical trials investigating clopidogrel treatment at a dose of 75 mg per day were not able to show positive net effects for an extended intake in various clinical scenarios in the past.15,16 This has been explained related to certain specific nondrug class but substance-related drug effects uniquely inherent to ticagrelor by several groups in the field.
At the same time, although the various cardioprotective effects of ticagrelor observed in experimental studies have been confirmed in clinical trials, the incremental bleeding risk seen in patients treated with ticagrelor as compared to clopidogrel needs to be considered carefully during the therapeutic decision-making in clinical practice. This represents one of the major factors explaining why current guidelines still advise the use of clopidogrel as the P2Y12 receptor antagonist of choice after percutaneous coronary intervention in patients with non-ACS.5,6 However, interestingly, several very recent clinical trials for the first time were able to show positive effects of extended nonticagrelor P2Y12 receptor antagonist intake for longer than 1 year after an index event in specific, carefully selected subsets of patients also when treated with clopidogrel or prasugrel.17–19
Carefully weighting the increasing evidence proving incremental effects of ticagrelor on top of direct platelet inhibition-which are mostly positive but in certain cases can also be contrary regarding clinical outcome-one is forced to conclude that there is still a long way to go until drug-specific as well as dose-dependent effects of the several P2Y12 receptor antagonists, and their clinical implications in various clinical scenarios, are fully understood. Because both the cardioprotective and hemorrhagic effects were found to be a dose-dependent phenomenon, further randomized clinical trials designed to test not only the net clinical benefit of the several P2Y12 receptor antagonists but also respective ideal drug doses in various clinical scenarios and patient groups might provide important clinical information for revealing the maximal tolerable effective drug dosage with the minimal (bleeding) risk not only in ACS, but also other patient collectives. From the clinical perspective, P2Y12 receptor antagonists share several aspects with direct anticoagulants such as rivaroxaban. However, in contrast to P2Y12 receptor antagonists, rivaroxaban is used in a rising number of at least 4 different dosing schemes in many countries routinely today, proven to fit different indications and patient collectives by meeting the respective ideal risk-benefit ratio for each scenario.20 One might speculate whether certain specific mechanisms of action of ticagrelor, such as the impact on the NF-κB pathway described in the current study by Liu et al, also require a dosing of 90 (or even 60) mg twice daily or might require higher or lower drug doses, therefore, ie, potentially proving beneficial in patients with non-ACS or patients at high risk for bleedings. Despite their availability for many years, the race is still on regarding optimal P2Y12 receptor antagonist treatment in clinical practice.
REFERENCES
1. Sinha N. Ticagrelor: molecular discovery to clinical evidence: ticagrelor: a novel antiplatelet agent. Indian Heart J. 2012;64:497–502.
2. Pesarini G, Ariotti S, Ribichini F. Current antithrombotic therapy in patients with acute coronary syndromes undergoing percutaneous coronary interventions. Interv Cardiol. 2014;9:94–101.
3. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
4. Li DT, Li SB, Zheng JY, et al. Analysis of ticagrelor's cardio-protective effects on patients with ST-segment elevation acute coronary syndrome accompanied with diabetes. Open Med. 2019;14:234–240.
5. Roffi M, Patrono C, Collet JP, et al; ESC Scientific Document Group. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: task force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2016;37:267–315.
6. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2014;64:e139–e228.
7. Ye Y, Birnbaum GD, Perez-Polo JR, et al. Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction. Arterioscler Thromb Vasc Biol. 2015;35:1805–1814.
8. Vilahur G, Gutierrez M, Casani L, et al. Protective effects of ticagrelor on myocardial injury after infarction. Circulation. 2016;134:1708–1719.
9. Liu X, Wang Y, Zhang M, et al. Ticagrelor reduces ischemia-reperfusion injury via NF-κB dependent pathway in rats. J Cardiovasc Pharmacol. In press.
10. Liu X, Gu Y, Liu Y, et al. Ticagrelor attenuates myocardial ischaemia-reperfusion injury possibly through downregulating galectin-3 expression in the infarct area of rats. Br J Clin Pharmacol. 2018;84:1180–1186.
11. Sexton TR, Zhang G, Macaulay TE, et al. Ticagrelor reduces thromboinflammatory markers in patients with pneumonia. JACC Basic Transl Sci. 2018;3:435–449.
12. Nanhwan MK, Ling S, Kodakandla M, et al. Chronic treatment with ticagrelor limits myocardial infarct size: an adenosine and cyclooxygenase-2-dependent effect. Arterioscler Thromb Vasc Biol. 2014;34:2078–2085.
13. DiNicolantonio JJ, D'Ascenzo F, Tomek A, et al. Clopidogrel is safer than ticagrelor in regard to bleeds: a closer look at the PLATO trial. Int J Cardiol. 2013;168:1739–1744.
14. Bonaca MP, Bhatt DL, Cohen M, et al. PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372:1791–1800.
15. Helft G, Steg PG, Le Feuvre C, et al; OPTImal DUAL Antiplatelet Therapy Trial Investigators. Stopping or continuing clopidogrel 12 months after drug-eluting stent placement: the OPTIDUAL randomized trial. Eur Heart J. 2016;37:365–374.
16. Palmerini T, Della Riva D, Benedetto U, et al. Three, six, or twelve months of dual antiplatelet therapy after DES implantation in patients with or without acute coronary syndromes: an individual patient data pairwise and network meta-analysis of six randomized trials and 11,473 patients. Eur Heart J. 2017;38:1034–1043.
17. Chin CT, Neely B, Magnus Ohman E, et al; TRILOGY ACS Investigators. Time-varying effects of prasugrel versus clopidogrel on the long-term risks of stroke after acute coronary syndromes: results from the TRILOGY ACS trial. Stroke. 2016;47:1135–1139.
18. Udell JA, Bonaca MP, Collet JP, et al. Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials. Eur Heart J. 2016;37:390–399.
19. Cho SW, Park K, Ahn JH, et al. Extended clopidogrel therapy beyond 12 Months and long-term outcomes in patients with diabetes mellitus receiving coronary arterial second-generation drug-eluting stents. Am J Cardiol. 2018;122:705–711.
20. Eikelboom JW, Connolly SJ, Bosch J, et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377:1319–1330.
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Ticagrelor Reduces Ischemia-Reperfusion Injury Through the NF-κB–Dependent Pathway in Rats Abstract: We recently showed that ticagrelor reduced myocardial ischemia-reperfusion injury (IRI) and downregulated galectin-3 in the ischemic myocardium. This study tested the hypothesis that ticagrelor could reduce IRI through the NF-κB pathway. Rats were randomly divided into sham-operated group, placebo group (gastric administration of saline after IRI), ticagrelor group (gastric administration of ticagrelor after left anterior descending artery ligation), dextran sodium sulfate (DSS) group (DSS was added to drinking water 7 days before IRI), and DSS + ticagrelor group (DSS was added to drinking water 7 days before IRI and gastric administration of ticagrelor after left anterior descending artery ligation). Ticagrelor significantly reduced the infarct size and plasma cTnI at 3 and 7 days after IRI, significantly downregulated protein and mRNA expressions of NF-κB and galectin-3, and mRNA expressions of IL-6 and TNF-α in the ischemic area at 24 hours, 3 and 7 days after IRI. Ticagrelor also significantly decreased plasma high-sensitivity C-reactive protein and NT-proBNP levels at 24 hours and 3 days after IRI. Furthermore, pretreatment with DSS blocked the beneficial effects of ticagrelor. Our study indicates that the cardioprotective effect of ticagrelor might be partly mediated by inhibiting the NF-κB pathway in this rat model of IRI. |
Melatonin-Mediated Pak2 Activation Reduces Cardiomyocyte Death Through Suppressing Hypoxia Reoxygenation Injury–Induced Endoplasmic Reticulum Stress Abstract: Cardiac reperfusion injury has been found to be associated with endoplasmic reticulum (ER) stress. Recently, p21-activated kinase 2 (Pak2) has been identified as a primary mediator of ER stress in chronic myocardial injury. Melatonin, a biological clock–related hormone, has been demonstrated to attenuate heart reperfusion burden by modulating ER stress and mitochondrial function. The aim of our study was to explore whether reperfusion-induced ER stress is modulated by melatonin through Pak2. Hypoxia reoxygenation (HR) was used in vitro to mimic reperfusion injury in cardiomyocytes. ER stress, oxidative stress, calcium overload, and cell death were measured through Western blotting, enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, and immunofluorescence with the assistance of siRNA transfection and pathway blocker treatment. The results of our study demonstrated that HR decreased the levels of Pak2 in cardiomyocytes in vitro, and inactivation of Pak2 was associated with ER stress, oxidative stress, calcium overload, caspase-12 activation, and cardiomyocytes apoptosis in vitro. Interestingly, melatonin treatment attenuated HR-mediated ER stress, redox imbalance, calcium overload, and caspase-12–related cardiomyocytes apoptosis, and these protective effects were dependent on Pak2 upregulation. Knockdown of Pak2 abolished the beneficial actions exerted by melatonin on HR-treated cardiomyocytes in vitro. Finally, we found that melatonin reversed Pak2 expression by activating the AMPK pathway and blockade of the AMPK pathway suppressed Pak2 upregulation and cardiomyocytes survival induced by melatonin in the presence of HR stress. Overall, our study reports that the AMPK-Pak2 axis, a novel signaling pathway modulated by melatonin, sends prosurvival signals for cardiomyocytes reperfusion injury through attenuation of ER stress in vitro. |
Cinnamaldehyde Ameliorates High-Glucose–Induced Oxidative Stress and Cardiomyocyte Injury Through Transient Receptor Potential Ankyrin 1 Abstract: Oxidative stress plays a critical role in diabetic cardiomyopathy. Transient receptor potential ankyrin subtype 1 (TRPA1) has antioxidative property. In this study, we tested whether activation of TRPA1 with cinnamaldehyde protects against high-glucose–induced cardiomyocyte injury. Cinnamaldehyde remarkably decreased high-glucose–induced mitochondrial superoxide overproduction, upregulation of nitrotyrosine, P22phox, and P47phox, and apoptosis in cultured H9C2 cardiomyocytes (P < 0.01), which were abolished by a TRPA1 antagonist HC030031 (P < 0.01). Nrf2 and its induced genes heme oxygenase-1 (HO-1), glutathione peroxidase-1 (GPx-1), and quinone oxidoreductase-1 (NQO-1) were slightly increased by high glucose (P < 0.01) and further upregulated by cinnamaldehyde (P < 0.05 or P < 0.01). Feeding with cinnamaldehyde (0.02%)-containing diet for 12 weeks significantly decreased cardiac nitrotyrosine levels (P < 0.01), fibrosis, and cardiomyocyte hypertrophy (P < 0.05), while increased expression of antioxidative enzymes (HO-1, GPx-1, NQO-1, and catalase) (P < 0.01) in the myocardial tissue of db/db diabetic mice. These results suggest that cinnamaldehyde protects against high-glucose–induced oxidative damage of cardiomyocytes likely through the TRPA1/Nrf2 pathway. |
Low-Dose Adrenaline Reduces Blood Pressure Acutely in Anesthetized Pigs Through a β2-Adrenergic Pathway Abstract: Adrenaline (epinephrine) is one of the prime messengers of the fight-or-flight response, favoring the activation of β-adrenergic receptors. Although general vasoconstriction to nonessential tissues is imperative, the vasodilatory effect of β-adrenergic receptor activation contends with this. We aimed to determine the dose-dependent effects of adrenaline on hemodynamics and to test whether adrenaline could lower blood pressure (BP) through a β2-adrenergic pathway. Nineteen Danish landrace pigs were used to pharmacologically probe the hemodynamic effect of adrenaline. Pigs were anesthetized, intubated, and electrocardiogram, systolic BP (SBP), diastolic BP (DBP), and left ventricular pressure (LVP) were monitored continuously. First, we tested the dose-dependent effects of adrenaline (0.01–10 µg/kg). Second, we determined the response to adrenaline (0.3 µg/kg) after atropine, prazosin, and propranolol pretreatment. Finally, we tested the hemodynamic effect of salbutamol in a subset of pigs. All doses of adrenaline increased heart rate, while BP showed a biphasic response: At low doses, adrenaline decreased SBP from 118 ± 3 to 106 ± 4 mm Hg (n = 15; P < 0.05) and DBP from 86 ± 3 to 71 ± 3 (n = 15; P < 0.05), while at high doses, SBP and DBP increased. LVP showed a similar pattern, with a tendency of decreased pressure at low doses, and an increased pressure at high doses (P < 0.05). Pretreatment with autonomic blockers revealed that the increase in BP was due to α-adrenergic activity, while the decrease was due to β-adrenergic activity. In confirmation, β-adrenergic activation through salbutamol showed a similar decrease in SBP, DBP, and LVP. We conclude that adrenaline dose-dependently increases heart rate, while producing a biphasic response in BP with a decrease at low doses and an increase at high doses in an anesthetized, large-animal model. |
Vascular Protection and Decongestion Without Renin–Angiotensin–Aldosterone System Stimulation Mediated by a Novel Dual-Acting Vasopressin V1a/V2 Receptor Antagonist Abstract: Increased plasma vasopressin levels have been shown to be associated with the progression of congestive heart failure. Vasopressin mediates water retention by renal tubular V2 receptor activation as well as vasoconstriction, cardiac hypertrophy, and fibrosis through V1a receptor activation. Therefore, we developed a novel, dual-acting vasopressin receptor antagonist, BAY 1753011, with almost identical Ki-values of 0.5 nM at the human V1a receptor and 0.6 nM at the human V2 receptor as determined in radioactive binding assays. Renal V2 antagonism by BAY 1753011 was compared with the loop diuretic furosemide in acute diuresis experiments in conscious rats. Similar diuretic efficacy was found with 300-mg/kg furosemide (maximal diuretic response) and 0.1-mg/kg BAY 1753011. Furosemide dose-dependently induced plasma renin and angiotensin I levels, while an equiefficient diuretic BAY 1753011 dose did not activate the renin–angiotensin system. BAY 1753011 dose-dependently decreased the vasopressin-induced expression of the profibrotic/hypertrophic marker plasminogen activator inhibitor-1 and osteopontin in rat cardiomyocytes, while the selective V2 antagonist satavaptan was without any effect. The combined vascular V1a-mediated and renal V2-mediated properties as well as the antihypertrophic/antifibrotic activity enable BAY 1753011 to become a viable treatment option for oral chronic treatment of congestive heart failure. |
Physcion 8-O-β-Glucopyranoside Alleviates Oxidized Low-Density Lipoprotein-Induced Human Umbilical Vein Endothelial Cell Injury by Inducing Autophagy Through AMPK/SIRT1 Signaling Aim: Vascular endothelial cell dysfunction plays a crucial role in the initiation and development of atherosclerosis. Physcion 8-O-β-glucopyranoside (PG), an anthraquinone extracted from Polygonum cuspidatum, has a number of pharmacological functions. The aim of this study was to elucidate the protective effects of PG against oxidized low-density lipoprotein (ox-LDL) in VECs. Methods and Materials: Human umbilical vein endothelial cells (HUVECs) were used as the in vitro model. Cell viability and apoptosis were, respectively, assessed by CCK-8 assay and Annexin-V/PI staining. Formation of autophagosomes was visualized by acridine orange staining, and the autophagy flux was tracked after infecting the cells with the mRFP-GFP-LC3 adenovirus. The expression levels of various apoptosis and autophagy-associated marker proteins were detected by Western blotting. Results: Pretreatment with PG protected the HUVECs from ox-LDL–induced apoptosis. In addition, PG promoted autophagy in HUVECs, which was responsible for its antiapoptotic effects. Finally, activation of AMPK/SIRT1 signaling was upstream of PG-induced autophagy. Conclusions: PG has potential pharmacological effects against oxidative damage–induced HUVEC injury through inducing AMPK/SIRT1-mediated autophagy. |
miR-3188 (rs7247237-C>T) Single-Nucleotide Polymorphism Is Associated With the Incidence of Vascular Complications in Chinese Patients With Type 2 Diabetes Abstract: miR-3188, one of the earliest discovered microRNAs, is involved in regulating the mTOR-p-PI3K/AKT pathway, thus affecting the progression of diabetic complications. In this study, we observed that the miR-3188 (rs7247237-C>T) polymorphism not only affected the production of nitric oxide (NO) production in endothelial cells, but also significantly associated with the incidence of vascular complications in Chinese patients with type 2 diabetes. Mechanistic analyses indicate that miR-3188 (rs7247237-T) polymorphism inhibited its own expression and upregulated the expression of gstm1 and trib3, which impairs NO production in human endothelial cells through inactivating AKT/eNOS signal transduction pathway. In addition, our clinical retrospective study indicated that, compared with patients with the CC genotype (n = 351), patients with rs7247237 TT + CT genotypes (n = 580) exhibited an increased risk of major vascular events during intensive glucose control treatment (hazard ratio = 1.560; 95% CI: 1.055–2.307, P = 0.025). Simultaneously, the risk of major vascular events was marginally decreased in patients with the CC genotype during intensive glucose control treatment compared with standard treatment (hazard ratio = 0.666; 95% CI: 0.433–1.016, P = 0.053). Our findings indicate that the miR-3188 (rs7247237-C>T) polymorphism is associated with the incidence of vascular complications in Chinese patients with type 2 diabetes, likely due to its remarkable effect on miR-3188 expression. |
Δευτέρα 8 Ιουλίου 2019
Cardiovascular Pharmacology - Current Issue
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