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Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice.

ABSTRACT: Limitation of infarct size is a major goal of therapy for acute coronary syndromes, and research has focused on achieving rapid patency of infarct-related vessels. However, new understandings of epigenetic modifications during ischemia suggest additional targeted approaches that have not been extensively explored. Here, we show that ischemia induces histone deacetylase (HDAC) activity in the heart with deacetylation of histones H3/4 in vitro and in vivo. We show, utilizing a standard murine model of ischemia-reperfusion, that chemical HDAC inhibitors significantly reduce infarct area, even when delivered 1 h after the ischemic insult. We demonstrate that HDAC inhibitors prevent ischemia-induced activation of gene programs that include hypoxia inducible factor-1alpha, cell death, and vascular permeability in vivo and in vitro, thus providing potential mechanisms to explain reduced vascular leak and myocardial injury. In vitro, siRNA knockdown experiments implicate HDAC4 as a mediator of the effects in ischemic cardiac myocytes. These results demonstrate that HDAC inhibitors alter the response to ischemic injury in the heart and reduce infarct size, suggesting novel therapeutic approaches for acute coronary syndromes.

SUBMITTER: Granger A

PROVIDER: S-EPMC2537432 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice.

Granger Anne A Abdullah Ibrahim I Huebner Faith F Stout Andrea A Wang Tao T Huebner Thomas T Epstein Jonathan A JA Gruber Peter J PJ

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20080707 10

Limitation of infarct size is a major goal of therapy for acute coronary syndromes, and research has focused on achieving rapid patency of infarct-related vessels. However, new understandings of epigenetic modifications during ischemia suggest additional targeted approaches that have not been extensively explored. Here, we show that ischemia induces histone deacetylase (HDAC) activity in the heart with deacetylation of histones H3/4 in vitro and in vivo. We show, utilizing a standard murine mode ...[more]

PMID: 18606865

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Project description:BackgroundReperfusion of ischemic tissue has adverse impact on the myocardium. Dexmedetomidine (Dex) is a α2-adrenergic receptor (α2-AR) agonist with sedative and analgesic effects. Macrophage migration inhibition factor (MIF) is a pressure-regulating cytokine and is responsible for inflammatory and immune diseases. This study aims to reveal the consequences of Dex on myocardial ischemia-reperfusion injury (IRI) in young mice.MethodsFifty mice were raised and examined. At the end of the experiment, all mice were euthanized. The anterior descending department of the left coronary artery in mice was under ischemia for 60 min, then the ligation line was released and reperfused for 120 min to establish the IRI model. Mice were randomly divided into Sham, control, treatment using 4,5-dihydro-3-(4-hydroxyphenyl)-5-isoxazoleacetic acid (ISO-1), Dex treatment, and Dex combined ISO-1 treatment groups. Interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF-α) were determined by enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) and ATP levels were recorded. The expressions of MIF, P-adenosine monophosphate-activated kinase α (AMPKα), glucose transporter (GLUT)4, Bax and Bcl-2 were detected by Western Blot (WB). Hematoxylin and Eosin (H&E) staining was used to study cell morphology. Apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. Echocardiography was carried out at the end of reperfusion, and the infarct size was calculated by Electron microscopy.ResultsI/R + Dex group showed significantly increased IL-6 and TNF-α levels and reduced myocardial cell necrosis and apoptosis. H&E staining showed alleviated myocardial disorder, myocardial cell swelling, myocardial fiber fracture, and inflammatory cell infiltration in I/R + Dex group. Myocardial cell necrosis and apoptosis were significantly reduced in I/R + Dex group. ATP level in myocardial tissue of mice in I/R group was substantially decreased, while that in Dex group was increased. WB results showed that MIF, P-AMPK α, GLUT4 and Bcl-2 levels were increased and Bax levels were decreased in I/R + Dex group.ConclusionDex may exert myocardial protection in young mice through MIF/AMPK/GLUT4 axis.

Project description:ObjectiveHumanin (HN), an endogenous antiapoptotic peptide, has previously been shown to protect against Alzheimer's disease and a variety of cellular insults. We evaluated the effects of a potent analog of HN (HNG) in an in vivo murine model of myocardial ischemia and reperfusion.Methods and resultsMale C57BL6/J mice (8 to 10 week old) were subjected to 45 minutes of left coronary artery occlusion followed by a 24-hour reperfusion. HNG or vehicle was administered IP 1 hour prior or at the time of reperfusion. The extent of myocardial infarction per area-at-risk was evaluated at 24 hours using Evans Blue dye and 2-3-5-triphenyl tetrazolium chloride staining. Left ventricular function was evaluated at 1 week after ischemia using high-resolution, 2D echocardiography (VisualSonics Vevo 770). Myocardial cell signaling pathways and apoptotic markers were assessed at various time points (0 to 24 hours) following reperfusion. Cardiomyocyte survival and apoptosis in response to HNG were assessed in vitro. HNG reduced infarct size relative to the area-at-risk in a dose-dependent fashion, with a maximal reduction at the dose of 2 mg/kg. HNG therapy enhanced left ventricular ejection fraction and preserved postischemic left ventricular dimensions (end-diastolic and end-systolic), resulting in improved cardiac function. Treatment with HNG significantly increased phosphorylation of AMPK and phosphorylation of endothelial nitric oxide synthase in the heart and attenuated Bcl-2-associated X protein and B-cell lymphoma-2 levels following myocardial ischemia and reperfusion. HNG improved cardiomyocyte survival and decreased apoptosis in response to daunorubicin in vitro.ConclusionsThese data show that HNG provides cardioprotection in a mouse model of myocardial ischemia and reperfusion potentially through activation of AMPK-endothelial nitric oxide synthase-mediated signaling and regulation of apoptotic factors. HNG may represent a novel agent for the treatment of acute myocardial infarction.

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Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice.

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Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice.

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