Effects of Adiponectin on Diastolic Function in Mice Underwent Transverse Aorta ConstrictionAbstract
Diastolic dysfunction is common in various cardiovascular diseases, which could be affected by adiponectin (APN). Nevertheless, the effects of APN on diastolic dysfunction in pressure overload model induced by transverse aorta constriction (TAC) remain to be further elucidated. Here, we demonstrated that treatment of APN attenuated diastolic dysfunction and cardiac hypertrophy in TAC mice. Notably, APN also improved active relaxation of adult cardiomyocytes, increased N2BA/N2B ratios of titin isoform, and reduced collagen type I to type III ratio and lysyl oxidase (Lox) expressions in the myocardial tissue. Moreover, APN supplementation suppressed TAC-induced oxidative stress. In vitro, inhibition of AMPK by compound C (Cpc) abrogated the effect of APN on modulation of titin isoform shift and the anti-hypertrophic effect of APN on cardiomyocytes induced by AngII. In summary, our findings indicate that APN could attenuate diastolic dysfunction in TAC mice, which are at least partially mediated by AMPK pathway.
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Exercise Improves the Function of Endothelial Cells by MicroRNAAbstract
Vascular diseases induced by diabetes and obesity (e.g., atherosclerosis) are associated with insulin resistance (IR), which leads to endothelial cell dysfunction due to metabolic disorder and oxidative stress. Research conducted by Cai showed that exercise prevented the formation of aortic plaque by regulating miR-429 and its target resistin, thus might be a novel potential therapeutic strategy for cardiovascular diseases.
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TLR2-Dependent Reversible Oxidation of Connexin 43 at Cys260 Modifies Electrical Coupling After Experimental Myocardial Ischemia/ReperfusionAbstract
We have shown previously that during myocardial ischemia/reperfusion (MI/R), toll-like receptor 2 (TLR2) signaling regulates connexin 43 (Cx43) subcellular localization and function and dampens arrhythmia formation. We aimed to identify sites capable of TLR2-dependent redox modification within Cx43. Post-ischemic TLR2−/− or wild-type (WT) mouse hearts were analyzed by OxICAT. Cx43 was mutated to exclude redox modification and transfected into HL-1 cardiomyocytes (CM) that were challenged with a TLR2 agonist. We identified Cys260 of Cx43 to be susceptible to reversible oxidation MI/R; TLR2−/− leads to reduced H2O2 production in post-ischemic isolated mitochondria and subsequently reduced oxidation of Cx43 at Cys260. Cx43 was dephosphorylated in WT, while phosphorylation was preserved in TLR2−/−. Mutation of Cx43 (C260A) and lentiviral transfection in HL-1 CM accelerated pacemaker activity and reduced activity after TLR2 ligand stimulation. We here provide evidence for TLR2-dependent reversible oxidation of Cx43 at Cys260, which led to decreased Cx43 phosphorylation and affected CM pacemaker frequency and intercellular communication.
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Changes in Titin and Collagen Modulate Effects of Aerobic and Resistance Exercise on Diabetic Cardiac FunctionAbstract
Diastolic dysfunction is a common complication that occurs early in diabetes mellitus. Titin and collagen are two important regulators of myocardial passive tension, which contributes to diabetic myocardial diastolic dysfunction. Exercise therapy significantly improves the impaired diabetic cardiac function, but its benefits appear to depend on the type of exercise used. We investigated the effect of aerobic and resistance exercise on cardiac diastolic function in diabetic rats induced by high-fat diet combined with low-dose streptozotocin injection. Interestingly, although resistance training had a more pronounced effect on blood glucose control than did aerobic training in type 2 diabetic rats, improvements in cardiac diastolic parameters benefited more from aerobic training. Moreover, aerobic exercise did significantly increase the expression levels of titin and decrease collagen I, TGFβ1 expression level. In summary, out data suggest that aerobic exercise may improve diabetic cardiac function through changes in titin-dependent myocardial stiffness rather than collagen-dependent interstitial fibrosis.
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Kdm6A Protects Against Hypoxia-Induced Cardiomyocyte Apoptosis via H3K27me3 Demethylation of Ncx GeneAbstract
Molecular events involved in acute myocardial infarction (AMI) still remain unclear. A rat AMI model and cardiomyocytes cultured in vitro were used to mimic hypoxic conditions, and the profiles of histone methylation-related gene expression were explored. The demethylase Kdm6a expression was significantly upregulated in the rat AMI model and in hypoxia induction. The apoptosis rate of cardiomyocytes was significantly exacerbated when Kdm6a was knocked down. The expression of the Na+/Ca2+ exchanger (Ncx) was significantly upregulated in cardiomyocytes under hypoxia. Knockdown of Kdm6a downregulated the Ncx expression via enhancing H3K27me3 modification on Ncx gene promoter, and attenuated the intracellular calcium influx ability in cardiomyocytes as a consequence. Kdm6a regulates Ncx expression through reducing the H3K27me3 level on the Ncx promoter or enhancer. This finding provides a basis for further study of Kdm6a as a new regulator for AMI development.
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Plasma Complement Protein C3a Level Was Associated with Abdominal Aortic Calcification in Patients on HemodialysisAbstract
The complement system plays an important role in cardiovascular disease in patients on hemodialysis. Vascular calcification is also one of the major causes of cardiovascular disease. We want to investigate the relationship between complement activation and vascular calcification in dialyzed patients. One hundred eight hemodialysis patients and 65 heathy controls were enrolled prospectively. Plasma C3a, C5a, mannose-binding lectin (MBL), and membrane attack complex (MAC or C5b-9) levels were detected using ELISA. Plasma C3c, fB, fH, C1q, and C4 levels were measured by immunity transmission turbidity. Abdominal aortic calcification (AAC) was measured by abdomen lateral plain radiograph, and the AAC score was calculated. We identified increased level of MBL and decreased level of C3c and complement factor B compared with normal control. However, C1q, complement factor H, and C4 levels remained at a similar level compared with individuals with normal renal function. The C3a and C5a levels increased, without change of MAC. Forty two of 108 HD patients had the AAC score. C3a levels were correlated with AAC score (r = 0.461, p = 0.002). The median C3a concentration was 238.72 (196.96, 323.41) ng/mL. When evaluated as AAC categories (≤ 4, > 5) with ordinal logistic regression, univariate analyses revealed that higher C3a levels were associated with severe AAC, while multivariate analyses adjusted for age, sex, and calcium level showed that higher C3a levels (OR, 6.28 (1.25–31.69); p = 0.03) were associated with severe AAC. The areas under the curve (AUC) for C3a to diagnose severe abdominal aortic calcification were 0.75(0.58–0.92, 0.01). The complement system was activated in patients on hemodialysis. Higher C3a levels are independently associated with severe AAC. Plasma C3a might have a diagnostic value for the severe AAC in HD patients.
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Induced Pluripotent Stem Cell–Derived Cardiomyocytes from a Patient with MYL2-R58Q-Mediated Apical Hypertrophic Cardiomyopathy Show Hypertrophy, Myofibrillar Disarray, and Calcium PerturbationsAbstract
Hypertrophic cardiomyopathy (HCM), characterized by unexplained left ventricular hypertrophy, is one of the most common heritable cardiovascular diseases. The myosin regulatory light chain (MYL2) mutation R58Q has been associated with severe cardiac hypertrophy and sudden cardiac death (SCD). Herein, we provide the first patient-specific, induced pluripotent stem cell–derived cardiomyocyte (iPSC-CM) model of MYL2-R58Q. The MYL2-R58Q iPSC-CMs were nearly 30% larger than control iPSC-CMs at day 60. The percentage of myofibrillar disarray and cells with irregular beating in MYL2-R58Q iPSC-CMs was significantly higher than that in control cells. MYL2-R58Q iPSC-CMs had significantly decreased peak ΔF/F0 of calcium transients and delayed decay time than controls. Additionally, the L-type Ca2+ channel (LTCC) (ICa,L) density at 0 mV was reduced significantly by 45.3%. Overall, the MYL2-R58Q iPSC-CMs recapitulated the HCM phenotype by exhibiting hypertrophy, myofibrillar disarray, increased irregular beating, decreased [Ca2+]i transients, and unexpectedly a nearly 50% reduction in LTCC peak current.
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Identification of miR-143 as a Major Contributor for Human Stenotic Aortic Valve DiseaseAbstract
Calcification of aortic valves leads to aortic stenosis mainly in elderly individuals, but the underlying molecular mechanisms are still not understood. Here, we studied microRNA (miR, miRNA) expression and function in healthy and stenotic human aortic valves. We identified miR-21, miR-24, and miR-143 to be highly upregulated in stenotic aortic valves. Using luciferase reporter systems, we found direct binding of miR-143 to the 3′UTR region of the matrix gla protein (MGP), which in turn is a key factor to sustain homeostasis in aortic valves. In subsequent experiments, we demonstrated a therapeutic potential of miRNA regulation during calcification in cardiac valvular interstitial cells. Collectively, our data provide evidence that deregulated miR expression contributes to the development of stenotic valve disease and thus form novel therapeutic opportunities of this severe cardiovascular disease.
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Long Noncoding RNA-CERNA1 Stabilized Atherosclerotic Plaques in apolipoprotein E −/− MiceAbstract
Atherosclerosis is predicted to be the primary cause of death in the world by 2020. Changes in atherosclerotic plaque composition will lead to acute coronary syndromes. Although the studies on the molecular mechanisms of long noncoding RNA (lncRNA) are in-depth in molecular and cell levels, the in vivo research which studied the knowledge about lncRNAs in the regulation of plaque composition is still sparse. In this study, in order to investigate how a new lncRNA, CERNA1, regulates the composition of atherosclerotic plaques, we overexpressed CERNA1 in apolipoprotein E−/− (Apo E−/−) mice and analyzed the role of CERNA1 in atherosclerotic plaque stabilization. The results showed that CERNA1 inhibited the apoptosis of VSMCs and anti-inflammatory macrophages through increasing API5 level and further stabilized the atherosclerotic plaques. This discovery provided a novel therapeutic target for atherosclerosis.
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Adipokine Dysregulation and Insulin Resistance with Atherosclerotic Vascular Disease: Metabolic Syndrome or Independent Sequelae?Abstract
Adipokine dysregulation and insulin resistance are two hallmark sequelae attributed to the current clinical definition of metabolic syndrome (MetS) that are also linked to atherosclerotic vascular disease. Here, we critically discuss the underlying pathophysiological mechanisms and the interplay between the two sequelae. Adipokine dysregulation is involved with decreased nitric oxide, vascular inflammation, and insulin resistance in itself to promote atherosclerosis. Insulin resistance is involved with endothelial dysfunction by direct and indirect mechanisms that also promote vascular inflammation and atherosclerosis. These mechanisms are discussed in atherosclerosis irrespective of MetS, and to evaluate the possibility of synergism in MetS. High retinol-binding protein-4 (RBP-4) and low cholesterol efflux in MetS may provide evidence of possible synergism and elevated atherosclerotic risk. An adverse adipokine panel that includes fetuin-A and adiponectin can potentially assess atherosclerotic risk in even those without MetS. Genetic possibilities may exist in atherosclerotic vascular diseases secondary to insulin resistance.
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ΩτοΡινοΛαρυγγολόγος Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,
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Κυριακή 20 Οκτωβρίου 2019
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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,
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00302841026182,
00306932607174,
alsfakia@gmail.com,
Anapafseos 5 Agios Nikolaos 72100 Crete Greece,
Medicine by Alexandros G. Sfakianakis,
Telephone consultation 11855 int 1193
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