Cardiovascular Pharmacology

Inhibition of Endothelial Dysfunction by Dietary Flavonoids and Preventive Effects Against Cardiovascular Disease Abstract: Cardiovascular disease (CVD), such as stroke, ischemic heart disease, and heart failure, accounts for many deaths, and its increasing incidence is a worldwide concern. Accumulating evidence suggests that the elevated risk of CVD caused by dysfunction of vascular endothelial cells and resultant arteriosclerosis can be mitigated by increased consumption of fruits and vegetables. These foods contain phytochemicals such as polyphenols and carotenoids, as well as dietary fiber. Flavonoids of the polyphenol class are found in vegetables, fruits, grains, bark, roots, stems, flowers, tea, and wine. Several studies have indicated that flavonoids reduce CVD mortality by inhibiting endothelial dysfunction. Flavonoids have a common carbon skeleton and are classified as flavonols, flavones, flavanols, flavanones, anthocyanidins, and isoflavones. In this review, we discuss recent progress in identifying the mechanisms by which dietary flavonoids improve vascular endothelial cell function. Furthermore, we describe the beneficial role that these flavonoids may play in preventing CVD caused by endothelial dysfunction-related atherosclerosis.

Noncoding RNAs in Atrial Fibrillation: Current Status and Prospect Abstract: Atrial fibrillation (AF) is an important cause of cardiovascular morbidity and mortality. Current therapies for AF are ineffective, mainly due to incomplete understanding of the pathogenesis of AF. Atrial remodeling contributes to the occurrence and progression of AF, but molecular mechanisms underlying AF remain unclear. Noncoding RNAs, including microRNAs, long noncoding RNAs and circular RNAs, are now considered to play an important role in the pathophysiology of AF. In this review, we summarize recent evidence supporting the role of noncoding RNAs in AF and highlight their diagnostic and prognostic applications as potential biomarkers and therapeutic strategies.

Neurovascular Effects of Perivascular Adipose Tissue: Regulation of Sympathetic-Sensory Communication No abstract available

Perivascular Adipose Tissue Modulation of Neurogenic Vasorelaxation of Rat Mesenteric Arteries Abstract: Perivascular sympathetic-sensory interactions have been shown to regulate calcitonin gene-related peptide (CGRP)-mediated vasodilation in rats. We investigated whether perivascular adipose tissue (PVAT) modulates the neurogenic vasorelaxation of isolated rat mesenteric arteries. Mesenteric arterial rings were prepared with or without PVAT (PVAT+ or PVAT−) and with either an intact or denuded endothelium (EC+ or EC−). The results of myography analysis revealed that vasocontraction to phenylephrine was highest in EC−PVAT−, lowest in EC+PVAT+, and intermediate in EC−PVAT+ and EC+PVAT−. Transmural nerve stimulation (TNS) induced the tetrodotoxin-sensitive relaxation of the phenylephrine-precontracted mesenteric arteries. However, nicotine induced minor relaxation in EC−PVAT+, whereas vasorelaxation was significantly enhanced in EC−PVAT−. Nicotine-induced vasorelaxation was insensitive to propranolol and also significantly lower in sympathetically-denervated and guanethidine-treated EC−PVAT−, whereas TNS-induced vasorelaxation persisted. In EC−PVAT− depleted of CGRP via capsaicin, nicotine- and TNS-induced vasorelaxation was almost absent. Lowering the pH of Krebs' solution using HCl led to pH-dependent vasorelaxation that was sensitive to CGRP8-37. Furthermore, nicotine-induced relaxation of EC−PVAT−, which was not affected by leptin, was blocked by methyl palmitate. Methyl palmitate did not affect TNS- or HCl-induced vasorelaxation. These results suggest that PVAT plays a modulatory role in regulating sympathetic-sensory interaction-mediated CGRPergic vasorelaxation via the release of methyl palmitate.

Important Roles of Endothelium-Dependent Hyperpolarization in Coronary Microcirculation and Cardiac Diastolic Function in Mice Abstract: Endothelium-dependent hyperpolarization (EDH) factor is one of endothelium-derived relaxing factors and plays important roles especially in microvessels. We have previously demonstrated that endothelium-derived hydrogen peroxide (H2O2) is an EDH factor produced by all types of nitric oxide synthases (NOSs), including endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS. Recent studies have suggested the association between coronary microvascular dysfunction and cardiac diastolic dysfunction. However, the role of EDH in this issue remains to be fully elucidated. We thus examined whether EDH plays an important role in coronary microcirculation and if so, whether endothelial dysfunction, especially impaired EDH, is involved in the pathogenesis of cardiac diastolic dysfunction in mice. Using a Langendorff-perfused heart experiment, we examined the increase in coronary flow in response to bradykinin in the presence of indomethacin and Nω-nitro-L-arginine (EDH condition) in wild-type, eNOS-knockout (KO), and nNOS/eNOS-double-KO mice. Compared with wild-type mice, EDH-mediated relaxations were increased in eNOS-KO mice but were significantly reduced in n/eNOS-KO mice. Catalase, a specific H2O2 scavenger, markedly inhibited EDH-mediated relaxations in all 3 genotypes, indicating compensatory roles of nNOS-derived H2O2 as an EDH factor in coronary microcirculation. Although both eNOS-KO and n/eNOS-KO mice exhibited similar extents of cardiac morphological changes, only n/eNOS-KO mice exhibited cardiac diastolic dysfunction. The expression of oxidized protein kinase G I-α (PKGIα) in the heart was significantly increased in eNOS-KO mice compared with n/eNOS-KO mice. These results indicate that EDH/H2O2 plays important roles in maintaining coronary microcirculation and cardiac diastolic function through oxidative PKGIα activation.

Direct Oral Anticoagulant Use After Transcatheter Aortic Valve Replacement: A Case Series Background: Use of an anticoagulant after transcatheter aortic valve replacement (TAVR) has been increasing in practice after noted leaflet thrombosis on dual antiplatelet therapy. As the use of anticoagulation increases so does the number of poor warfarin candidates or warfarin intolerant patients. While direct oral anticoagulant (DOAC) use is increasing for other indications, there is a paucity of data for use after TAVR. The objective of this case series is to add to the available evidence for patients who may require a DOAC after TAVR. Methods: A single-center, retrospective observational case series was conducted including adults 18 years of age and older who received a DOAC after TAVR between November 2008 and June 2018 at Mayo Clinic Hospital—Rochester. All patients were identified as part of the Society of Thoracic Surgeons database. Results: Twenty-one patients were identified as having received a DOAC after TAVR. Median age was 83.5 years (interquartile range 77–87), with 71% males. Within this cohort, 20 patients (95.2%) had an alternative indication for anticoagulation of either atrial fibrillation or atrial flutter. Apixaban was prescribed in 66.7% of patients, followed by rivaroxaban (14.3%), dabigatran (9.5%), and edoxaban (4.8%). No thromboembolic events were reported. Three patients experienced a bleeding event, of which only 2 occurred in the 3 months immediately after TAVR. Conclusions: DOAC therapy after TAVR was generally safe and well tolerated. Taken in context of other retrospective studies, these data suggest that the presence of valvular heart disease, specifically TAVR in this case, should not preclude the use of DOACs.

Berberine Attenuates Cholesterol Accumulation in Macrophage Foam Cells by Suppressing AP-1 Activity and Activation of the Nrf2/HO-1 Pathway Abstract: Atherosclerosis is a chronic inflammation condition resulting from the interaction between lipoproteins, monocyte-derived macrophages, T lymphocytes, and other cellular elements in the arterial wall. Macrophage-derived foam cells play a key role in both early and advanced stage of atherosclerosis. Previous studies have shown that berberine could inhibit foam cell formation and prevent experimental atherosclerosis. However, its underlying molecular mechanisms have not been fully clarified. In this study, we explored the cholesterol-lowering effects of berberine in macrophage-derived foam cells and investigated its possible mechanisms in prevention and treatment of atherosclerosis. Here, we demonstrated that berberine could inhibit atherosclerosis in apolipoprotein E-deficient mice and induce cholesterol reduction as well as decrease the content of macrophages. Berberine can regulate oxLDL uptake and cholesterol efflux, thus suppresses foam cell formation. Mechanisms study showed that berberine can suppress scavenger receptor expression via inhibiting the activity of AP-1 and upregulate ATP-binding cassette transporter via activating Nrf2/HO-1 signaling in human macrophage. In summary, berberine significantly inhibits atherosclerotic disease development by regulating lipid homeostasis and suppressing macrophage foam cell formation.

Activation of Cannabinoid Receptors Attenuates Endothelin-1–Induced Mitochondrial Dysfunction in Rat Ventricular Myocytes Abstract: Evidence suggests that the activation of the endocannabinoid system offers cardioprotection. Aberrant energy production by impaired mitochondria purportedly contributes to various aspects of cardiovascular disease. We investigated whether cannabinoid (CB) receptor activation would attenuate mitochondrial dysfunction induced by endothelin-1 (ET1). Acute exposure to ET1 (4 hours) in the presence of palmitate as primary energy substrate induced mitochondrial membrane depolarization and decreased mitochondrial bioenergetics and expression of genes related to fatty acid oxidation (ie, peroxisome proliferator–activated receptor-gamma coactivator-1α, a driver of mitochondrial biogenesis, and carnitine palmitoyltransferase-1β, facilitator of fatty acid uptake). A CB1/CB2 dual agonist with limited brain penetration, CB-13, corrected these parameters. AMP-activated protein kinase (AMPK), an important regulator of energy homeostasis, mediated the ability of CB-13 to rescue mitochondrial function. In fact, the ability of CB-13 to rescue fatty acid oxidation–related bioenergetics, as well as expression of proliferator-activated receptor-gamma coactivator-1α and carnitine palmitoyltransferase-1β, was abolished by pharmacological inhibition of AMPK using compound C and shRNA knockdown of AMPKα1/α2, respectively. Interventions that target CB/AMPK signaling might represent a novel therapeutic approach to address the multifactorial problem of cardiovascular disease.

Single Bolus Rosuvastatin Accelerates Calcium Uptake and Attenuates Conduction Inhomogeneity in Failing Rabbit Hearts With Regional Ischemia–Reperfusion Injury Abstract: Acute statin therapy reduces myocardial ischemia/reperfusion (IR) injury–induced ventricular fibrillation (VF), but the underlying electrophysiological mechanisms remain unclear. This study sought to investigate the antiarrhythmic effects of a single bolus rosuvastatin injection in failing rabbit hearts with IR injury and to unveil the underlying molecular mechanisms. Rabbits were divided into rosuvastatin, rosuvastatin + L-NAME, control, and L-NAME groups. Intravenous bolus rosuvastatin (0.5 mg/kg) and/or L-NAME (10 mg/kg) injections were administered 1 hour and 15 minutes before surgery, respectively. Heart failure was induced using rapid ventricular pacing. Under general anesthesia with isoflurane, an IR model was created by coronary artery ligation for 30 minutes, followed by reperfusion for 15 minutes. Plasma NO end product levels were measured during IR. Then, hearts were excised and Langendorff-perfused for optical mapping studies. Cardiac tissues were sampled for Western blot analysis. Rosuvastatin increased plasma NO levels during IR, which was abrogated by L-NAME. Spontaneous VF during IR was suppressed by rosuvastatin (P < 0.001). Intracellular calcium (Cai) decay and conduction velocity were significantly slower in the IR zone. Rosuvastatin accelerated Cai decay, ameliorated conduction inhomogeneity, and reduced the inducibility of spatially discordant alternans and VF significantly. Western blots revealed significantly higher expression of enhancing endothelial NO-synthase and phosphorylated enhancing endothelial NO-synthase proteins in the Rosuvastatin group. Furthermore, SERCA2a, phosphorylated connexin43, and phosphorylated phospholamban were downregulated in the IR zone, which was attenuated or reversed by rosuvastatin. Acute rosuvastatin therapy before ischemia reduced IR-induced VF by improving SERCA2a function and ameliorating conduction disturbance in the IR zone.

Chitosan Hydrogel Enhances the Therapeutic Efficacy of Bone Marrow–Derived Mesenchymal Stem Cells for Myocardial Infarction by Alleviating Vascular Endothelial Cell Pyroptosis Abstract: Myocardial infarction (MI) is one of the higher mortality rates, and current treatment can only delay the progression of the disease. Experiments have shown that cell therapy could improve cardiac function and mesenchymal stem cells (MSCs)-based therapies provide a great promising approach in the treatment of MI. However, low cell survival and engraftment restricts the successful application of MSCs for treating MI. Here, we explored whether co-transplantation of a chitosan (CS) thermosensitive hydrogel with bone marrow-derived MSCs (BMSCs) could optimize and maximize the therapeutic of BMSCs in a mouse model of MI. The fate of transplanted BMSCs was monitored by bioluminescence imaging, and the recovery of cardiac function was detected by echocardiogram. Our results proved that CS hydrogel enhanced the BMSCs' survival and the recovery of cardiac function by protecting the vascular endothelial cells. Further studies revealed that the increased number of vascular endothelial cells was due to the fact that transplanted BMSCs inhibited the inflammatory response and alleviated the pyroptosis of vascular endothelial cells. In conclusions, CS hydrogel improved the engraftment of transplanted BMSCs, ameliorated inflammatory responses, and further promoted functional recovery of heart by alleviating vascular endothelial cell pyroptosis.