Abstract 15524: The Methyltransferase Setd7 Drives Myocardial Ischemic Injury by Modulating the Hippo Pathway: A Study in Mice and Humans

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Samuele Ambrosini ◽  
Fabrizio Montecucco ◽  
Daniela Pedicino ◽  
Alexander Akhmedov ◽  
Shafeeq Ahmed Mohammed ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Mononuclear Cells ◽  
Hippo Pathway ◽  
Ischemic Heart ◽  
Ischemic Heart Failure ◽  
Peripheral Blood Mononuclear ◽  
Myocardial Oxidative Stress ◽  
Blood Mononuclear Cells ◽  
The Hippo Pathway

Introduction: Ischemic heart disease is a leading cause of death worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a significant number of MI patients develop heart failure. Protein methylation is emerging as a key biological signal implicated in the pathophysiology of cardiovascular (CV) disease. In this regard, the methyltransferase SETD7 was recently shown to methylate proteins relevant to CV homeostasis. Hypothesis: To investigate SETD7 role in myocardial ischemia-reperfusion (I/R) injury. Methods: Experiments were performed in neonatal rat ventricular myocytes (NRVM), SETD7 knockout mice (SETD7 -/- ) undergoing myocardial I/R injury, myocardial samples from patients with and without ischemic heart failure as well as peripheral blood mononuclear cells from patients with ST elevation MI (STEMI, n=25) and age-matched healthy controls (n=20). Results: Glucose deprivation (GD) in NRVM led to upregulation of SETD7 and direct mono-methylation of the Hippo signaling effector YAP. SETD7-dependent methylation of YAP led to its cytosolic retention thus impeding YAP binding to the promoter of pro-survival genes. Selective pharmacological inhibition of SETD7 by (R)-PFI-2 blunted YAP mono-methylation thereby restoring its nuclear retention. We show that YAP binds the promoter of antioxidant genes catalase and superoxide dismutase, thus preventing GD-induced mitochondrial oxidative stress, organelle swelling and apoptosis. Consistently, infarct size, myocardial oxidative stress and left ventricular dysfunction were reduced in SETD7 -/- mice undergoing I/R as compared to wild-type littermates. Of clinical relevance, we found that SETD7/YAP signaling was deregulated in myocardial samples from patients with ischemic heart failure as well as in peripheral blood mononuclear cells from STEMI patients. Conclusions: We demonstrate that SETD7-dependent methylation of YAP is an important mechanism underpinning myocardial oxidative stress, mitochondrial damage and apoptosis during ischemia. Pharmacological modulation of SETD7 by (R)-PFI-2 may represent a potential therapeutic approach to prevent myocardial ischemic damage through modulation of the Hippo pathway.

scholarly journals Reynoutrin Improves Ischemic Heart Failure in Rats Via Targeting S100A1

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenkai Yang ◽  
Hanjian Tu ◽  
Kai Tang ◽  
Haozhong Huang ◽  
Shi Ou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Function ◽  
Protein Expression ◽  
Myocardial Fibrosis ◽  
Ischemic Heart ◽  
Inflammatory Factors ◽  
Myocardial Tissue ◽  
Ischemic Heart Failure ◽  
Tgf Β1

This study investigated the effects of reynoutrin on the improvement of ischemic heart failure (IHF) and its possible mechanism in rats. The rat heart failure model was established by permanently ligating the left anterior descending coronary artery (LAD) and administering different doses of reynoutrin. Cardiac function, inflammatory factors releasing, oxidative stress, cardiomyocytes apoptosis, and myocardial fibrosis were evaluated. Western blotting was used to determine protein expression levels of S100 calcium-binding protein A1 (S100A1), matrix metallopeptidase 2(MMP2), MMP9, phosphorylated (p-) p65, and transforming growth factor -β1 (TGF-β1) in myocardial tissue of the left ventricle. Results showed that reynoutrin significantly improved cardiac function, suppressed the release of inflammatory factors, reduced oxidative stress, inhibited cardiomyocytes apoptosis, and attenuated myocardial fibrosis in rats with IHF. In rat myocardial tissue, permanent LAD-ligation resulted in a significant down-regulation in S100A1 expression, whereas reynoutrin significantly up-regulated S100A1 protein expression while down-regulating MMP2, MMP9, p-p65, and TGF-β1 expressions. However, when S100A1 was knocked down in myocardial tissue, the above-mentioned positive effects of reynoutrin were significantly reversed. Reynoutrin is a potential natural drug for the treatment of IHF, and its mechanism of action involves the up-regulation of S100A1 expression, thereby inhibiting expressions of MMPs and the transcriptional activity of nuclear factor kappa-B.

scholarly journals Gene expression profiles in peripheral blood mononuclear cells of chronic heart failure patients

2009 ◽  
Vol 38 (3) ◽  
pp. 233-240 ◽  
Author(s):  
Claudia Cappuzzello ◽  
Monica Napolitano ◽  
Diego Arcelli ◽  
Guido Melillo ◽  
Roberta Melchionna ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Chronic Heart Failure ◽  
Chemokine Receptor ◽  
Expression Profiling ◽  
Mononuclear Cells ◽  
Molecular Signature ◽  
Peripheral Blood Mononuclear ◽  
Control Subjects ◽  
Blood Mononuclear Cells

The present study was aimed at identifying chronic heart failure (CHF) biomarkers from peripheral blood mononuclear cells (PBMCs) in patients with ischemic (ICM) and nonischemic dilated (NIDCM) cardiomyopathy. PBMC gene expression profiling was performed by Affymetrix in two patient groups, 1) ICM ( n = 12) and 2) NIDCM ( n = 12) New York Heart Association (NYHA) III/IV CHF patients, vs. 3) age- and sex-matched control subjects ( n = 12). Extracted RNAs were then pooled and hybridized to a total of 11 microarrays. Gene ontology (GO) analysis separated gene profiling into functional classes. Prediction analysis of microarrays (PAM) and significance analysis of microarrays (SAM) were utilized in order to identify a molecular signature. Candidate markers were validated by quantitative real-time polymerase chain reaction. We identified a gene expression profiling that distinguished between CHF patients and control subjects. Interestingly, among the set of genes constituting the signature, chemokine receptor (CCR2, CX3CR1) and early growth response (EGR1, 2, 3) family members were found to be upregulated in CHF patients vs. control subjects and to be part of a gene network. Such findings were strengthened by the analysis of an additional 26 CHF patients ( n = 14 ICM and n = 12 NIDCM), which yielded similar results. The present study represents the first large-scale gene expression analysis of CHF patient PBMCs that identified a molecular signature of CHF and putative biomarkers of CHF, i.e., chemokine receptor and EGR family members. Furthermore, EGR1 expression levels can discriminate between ICM and NIDCM CHF patients.

scholarly journals Exercise-Induced Reductive Stress Is a Protective Mechanism against Oxidative Stress in Peripheral Blood Mononuclear Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Ypatios Spanidis ◽  
Aristidis S. Veskoukis ◽  
Christina Papanikolaou ◽  
Dimitrios Stagos ◽  
Alexandros Priftis ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Eccentric Exercise ◽  
Mononuclear Cells ◽  
Reductive Group ◽  
Redox Status ◽  
Protective Mechanism ◽  
Peripheral Blood Mononuclear ◽  
Reductive Stress ◽  
Blood Mononuclear Cells ◽  
Baseline Values

Eccentric exercise is a well-studied modality that induces oxidative stress and muscle damage. Furthermore, it promotes inflammatory response in which peripheral blood mononuclear cells (PBMCs) are the major mediators. Although free radicals are necessary in a specific range of concentrations, yet unknown, it remains unclear whether reductive redox status (i.e., increased antioxidant defenses and impaired free radical generation) is beneficial or not. Thus, the aim of the present investigation was to examine the effects of reductive stress and the impact of reduced glutathione (GSH) baseline values on the ability of PBMCs to counteract oxidative stress induced by a potent oxidative agent. PBMCs were isolated from the blood of subjects who performed eccentric exercise and treated with t-BOOH for 24 h. The subjects were clustered in the reductive and the oxidative group on the basis of increased or decreased GSH concentration postexercise compared to preexercise values, respectively. According to our results in PBMCs, lipid peroxidation levels as depicted by thiobarbituric acid reactive substances (TBARS) remained unchanged in the reductive group contrary to the observed enhancement in the oxidative group. In addition, GSH concentration and catalase activity increased in the reductive group, whereas they were not affected in the oxidative group. In conclusion, the effects of an oxidizing agent on the redox status of PBMCs isolated from the blood of athletes after acute eccentric exercise are dependent on the baseline values of GSH in erythrocytes. Otherwise, reductive stress defined by increased GSH levels is a protective mechanism, at least when followed by an oxidative stimulus.

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