Abstract 310: Inhibition of Class I Histone Deacetylase Activity Improves Left Ventricular Contractile Function and Cardiac Strain in Coronary Artery Occlusion-Induced Myocardial Infarction

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Harinath Kasiganesan ◽  
Ludivine Renaud ◽  
Santhosh K Mani ◽  
Chou C James ◽  
Rupak Mukherjee ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Histone Deacetylases ◽  
Contractile Function ◽  
Strain Analysis ◽  
Left Ventricular ◽  
Class I ◽  
Border Zones ◽  
Cardiac Strain ◽  
Class I Hdacs

Protection from coronary heart disease-induced damage of the myocardium during myocardial infarction (MI) injury has been a target of investigation for the development of innovative cardioprotective therapies. Histone deacetylases (HDACs) are a class of enzymes that affect the transcriptional regulation of genes during pathological conditions. We observed that class I/IIb HDAC activity was nearly 5 times greater in the 7-day post-MI LV when compared to the sham ventricles. In vitro inhibition studies indicated that the majority of increased activity was due to class I HDACs. Therefore we hypothesized that suppression of class I HDACs would prevent the pathophysiological changes occurring during MI, thus improving LV pump function in post-MI myocardium. CD-1 mice were administered with the a class I HDAC inhibitor pimelic diphenylamide (PD106) or vehicle immediately after induction of MI and the treatment continued every other day for 7 days post MI. LV end-diastolic volumes, expressed as change from pre-MI values, was significantly lower in the PD106 treated mice compared to vehicle treated mice. Further, the post-MI reduction in LV ejection faction was significantly attenuated in the PD106-treated mice compared to the MI alone group. Similarly, echo cardiac strain analysis showed improved LV strain and better coherence in contractile function among infarct and border zones in PD106 MI group compared to MI only. These unique findings demonstrate that class I HDAC inhibitors may provide a novel therapeutic means to attenuate adverse post-MI LV remodeling.

scholarly journals Effects of dietary omega–3 fatty acids on ventricular function in dogs with healed myocardial infarctions: in vivo and in vitro studies

2010 ◽  
Vol 298 (4) ◽  
pp. H1219-H1228 ◽  
Author(s):  
George E. Billman ◽  
Yoshinori Nishijima ◽  
Andriy E. Belevych ◽  
Dmitry Terentyev ◽  
Ying Xu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Fatty Acids ◽  
Ventricular Function ◽  
Contractile Function ◽  
Left Ventricular ◽  
Calcium Currents ◽  
Calcium Handling ◽  
Omega 3

Since omega–3 polyunsaturated fatty acids (n-3 PUFAs) can alter ventricular myocyte calcium handling, these fatty acids could adversely affect cardiac contractile function, particularly following myocardial infarction. Therefore, 4 wk after myocardial infarction, dogs were randomly assigned to either placebo (corn oil, 1 g/day, n = 16) or n-3 PUFAs supplement [docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) ethyl esters; 1, 2, or 4 g/day; n = 7, 8, and 12, respectively] groups. In vivo, ventricular function was evaluated by echocardiography before and after 3 mo of treatment. At the end of the 3-mo period, hearts were removed and in vitro function was evaluated using right ventricular trabeculae and isolated left ventricular myocytes. The treatment elicited significant ( P < 0.0001) dose-dependent increases (16.4-fold increase with 4 g/day) in left ventricular tissue and red blood cell n-3 PUFA levels (EPA + DHA, placebo, 0.42 ± 0.04; 1 g/day, 3.02 ± 0.23; 2 g/day, 3.63 ± 0.17; and 4 g/day, 6.97 ± 0.33%). Regardless of the dose, n-3 PUFA treatment did not alter ventricular function in the intact animal (e.g., 4 g/day, fractional shortening: pre, 42.9 ± 1.6 vs. post, 40.1 ± 1.7%; placebo: pre, 39.2 ± 1.3 vs. post, 38.4 ± 1.6%). The developed force per cross-sectional area, changes in length- and frequency-dependent behavior in contractile force, and the inotropic response to β-adrenoceptor activation were also similar for trabeculae obtained from placebo- or n-3 PUFA-treated dogs. Finally, calcium currents and calcium transients were the same in myocytes from n-3 PUFA- and placebo-treated dogs. Thus dietary n-3 PUFAs did not adversely alter either in vitro or in vivo ventricular contractile function in dogs with healed infarctions.

scholarly journals Slowing of cardiomyocyte Ca2+ release and contraction during heart failure progression in postinfarction mice

2009 ◽  
Vol 296 (4) ◽  
pp. H1069-H1079 ◽  
Author(s):  
Halvor K. Mørk ◽  
Ivar Sjaastad ◽  
Ole M. Sejersted ◽  
William E. Louch
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Contractile Function ◽  
Cardiac Contractility ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Shortening Velocity ◽  
Transient Time

Deterioration of cardiac contractility during congestive heart failure (CHF) is believed to involve decreased function of individual cardiomyocytes and may include reductions in contraction magnitude and/or kinetics. We examined the progression of in vivo and in vitro alterations in contractile function in CHF mice and investigated underlying alterations in Ca2+ homeostasis. Following induction of myocardial infarction (MI), mice with CHF were examined at early (1 wk post-MI) and chronic (10 wk post-MI) stages of disease development. Sham-operated mice served as controls. Global and local left ventricle function were assessed by echocardiography in sedated animals (∼2% isoflurane). Excitation-contraction coupling was examined in cardiomyocytes isolated from the viable septum. CHF progression between 1 and 10 wk post-MI resulted in increased mortality, development of hypertrophy, and deterioration of global left ventricular function. Local function in the noninfarcted myocardium also declined, as posterior wall shortening velocity was reduced in chronic CHF (1.2 ± 0.1 vs. 1.9 ± 0.2 cm/s in sham). Parallel alterations occurred in isolated cardiomyocytes since contraction and Ca2+ transient time to peak values were prolonged in chronic CHF (115 ± 6 and 158 ± 11% sham values, respectively). Surprisingly, contraction and Ca2+ transient magnitudes in CHF were larger than sham values at both time points, resulting from increased sarcoplasmic reticulum Ca2+ content and greater Ca2+ influx via L-type channels. We conclude that, in mice with CHF following myocardial infarction, declining myocardial function involves slowing of cardiomyocyte contraction without reduction in contraction magnitude. Corresponding alterations in Ca2+ transients suggest that slowing of Ca2+ release is a critical mediator of CHF progression.

Alterations to myofibrillar protein function in nonischemic regions of the heart early after myocardial infarction

2007 ◽  
Vol 293 (1) ◽  
pp. H654-H659 ◽  
Author(s):  
Vijay S. Rao ◽  
Laura R. La Bonte ◽  
Yaqin Xu ◽  
Zequan Yang ◽  
Brent A. French ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Protein Function ◽  
Molecular Mechanisms ◽  
Contractile Function ◽  
Left Ventricular ◽  
Myofibrillar Protein ◽  
In Vitro Motility Assay ◽  
Thin Filaments ◽  
Remote Zone

Remote-zone left ventricular dysfunction (LVD) contributes to global reductions in contractile function after localized myocardial infarction (MI). However, the molecular mechanisms underlying this form of LVD are not clear. This study tested the hypothesis that myofibrillar protein function is directly affected in remote-zone LVD early after MI. Cardiac myosin and native thin filaments were purified from mouse myocardium taken from both the nonnecrotic zone adjacent to and the nonischemic zone remote from an infarct induced by 1 h of coronary occlusion followed by 24 h of reperfusion. Thin filament velocities were measured using the in vitro motility assay. Results showed that overall function was significantly reduced in samples from both the adjacent (43 ± 12% of control, n = 7) and remote (53 ± 8% of control, n = 13) zones when compared with control proteins ( P < 0.05). Myosin from the remote zone propelled control thin filaments at reduced velocities similar to those measured above. In contrast, the Ca2+ sensitivity of remote-zone thin filaments over control myosin was unchanged from control thin filaments (half-maximal at pCa 6.32 ± 0.08 and 6.27 ± 0.06, respectively) but showed a 20% increase in velocity at saturating Ca2+ that parallels an increase in tropomyosin phosphorylation. Myosin dysfunction may be related to oxidation of cysteines in the myosin heavy chains or carbonylation of myosin binding protein-C. We hypothesize that phosphorylation of tropomyosin may serve a compensatory role, augmenting contraction during periods of oxidative stress when myosin function is compromised.

Abstract 443: Class I Histone Deacetylases Mediate Cardiac I/R Injury and Modify the Mitochondrial Acetylome

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Daniel J Herr ◽  
Sverre E Aune ◽  
Jennifer R Bethard ◽  
Lauren E Ball ◽  
Donald R Menick
Keyword(s):  
Mass Spectrometry ◽  
Reperfusion Injury ◽  
Histone Deacetylases ◽  
Cardiac Tissue ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Class I ◽  
Mass Spectrometry Analysis ◽  
Hdac Inhibition ◽  
Class I Hdacs

Although rapid reperfusion of ischemic tissue is the treatment of choice for myocardial infarction, a significant amount of damage occurs as a result of reperfusion itself. The role of epigenetic enzymes in modulating this damage has become an area of interest in basic cardiac research. Previously, we have shown that pharmacological inhibition of the class I histone deacetylases (HDACs) with MS-275 (entinostat) preserves left-ventricular (LV) function and substantially reduces the area of infarcted tissue in isolated rat hearts subjected to ischemia-reperfusion (IR) injury. Interestingly, we have also observed that class I HDAC inhibition during 60 minutes of reperfusion alone is sufficient to protect cardiac tissue viability following I/R injury. Therefore, we hypothesized that class I HDACs mediate reperfusion injury by modulating acetylation of non-canonical pathways. To examine this, hearts from male Sprague-Dawley rats were subjected to I/R injury +/- class I HDAC inhibition during reperfusion. We then performed mass spectrometry to analyze the changes in the acetylome between sham and I/R groups with and without class I HDAC inhibition. Unexpectedly, mass spectrometry analysis revealed significant changes in the acetylation state of multiple mitochondrial enzymes. Further biochemical studies show that class I HDACs localize to the mitochondrial fraction of cardiac tissue homogenates and may modulate mitochondrial acetylation by direct or indirect mechanisms. This study emphasizes the importance of exploring class I HDAC inhibitors for protection against ischemia-reperfusion injury.

scholarly journals Adropin-based dual treatment enhances the therapeutic potential of mesenchymal stem cells in rat myocardial infarction

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
HuiYa Li ◽  
DanQing Hu ◽  
Guilin Chen ◽  
DeDong Zheng ◽  
ShuMei Li ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Therapeutic Potential ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Paracrine Factors ◽  
Dual Treatment

AbstractBoth weak survival ability of stem cells and hostile microenvironment are dual dilemma for cell therapy. Adropin, a bioactive substance, has been demonstrated to be cytoprotective. We therefore hypothesized that adropin may produce dual protective effects on the therapeutic potential of stem cells in myocardial infarction by employing an adropin-based dual treatment of promoting stem cell survival in vitro and modifying microenvironment in vivo. In the current study, adropin (25 ng/ml) in vitro reduced hydrogen peroxide-induced apoptosis in rat bone marrow mesenchymal stem cells (MSCs) and improved MSCs survival with increased phosphorylation of Akt and extracellular regulated protein kinases (ERK) l/2. Adropin-induced cytoprotection was blocked by the inhibitors of Akt and ERK1/2. The left main coronary artery of rats was ligated for 3 or 28 days to induce myocardial infarction. Bromodeoxyuridine (BrdU)-labeled MSCs, which were in vitro pretreated with adropin, were in vivo intramyocardially injected after ischemia, following an intravenous injection of 0.2 mg/kg adropin (dual treatment). Compared with MSCs transplantation alone, the dual treatment with adropin reported a higher level of interleukin-10, a lower level of tumor necrosis factor-α and interleukin-1β in plasma at day 3, and higher left ventricular ejection fraction and expression of paracrine factors at day 28, with less myocardial fibrosis and higher capillary density, and produced more surviving BrdU-positive cells at day 3 and 28. In conclusion, our data evidence that adropin-based dual treatment may enhance the therapeutic potential of MSCs to repair myocardium through paracrine mechanism via the pro-survival pathways.

scholarly journals Functional Interaction between Class II Histone Deacetylases and ICP0 of Herpes Simplex Virus Type 1

2004 ◽  
Vol 78 (13) ◽  
pp. 6744-6757 ◽  
Author(s):  
Patrick Lomonte ◽  
Joëlle Thomas ◽  
Pascale Texier ◽  
Cécile Caron ◽  
Saadi Khochbin ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Histone Deacetylases ◽  
Class Ii ◽  
Class I ◽  
Transfected Cells ◽  
Amino Terminal ◽  
Simplex Virus ◽  
Class I Hdacs

ABSTRACT This study describes the physical and functional interactions between ICP0 of herpes simplex virus type 1 and class II histone deacetylases (HDACs) 4, 5, and 7. Class II HDACs are mainly known for their participation in the control of cell differentiation through the regulation of the activity of the transcription factor MEF2 (myocyte enhancer factor 2), implicated in muscle development and neuronal survival. Immunofluorescence experiments performed on transfected cells showed that ICP0 colocalizes with and reorganizes the nuclear distribution of ectopically expressed class I and II HDACs. In addition, endogenous HDAC4 and at least one of its binding partners, the corepressor protein SMRT (for silencing mediator of retinoid and thyroid receptor), undergo changes in their nuclear distribution in ICP0-transfected cells. As a result, during infection endogenous HDAC4 colocalizes with ICP0. Coimmunoprecipitation and glutathione S-transferase pull-down assays confirmed that class II but not class I HDACs specifically interacted with ICP0 through their amino-terminal regions. This region, which is not conserved in class I HDACs but homologous to the MITR (MEF2-interacting transcription repressor) protein, is responsible for the repression, in a deacetylase-independent manner, of MEF2 by sequestering it under an inactive form in the nucleus. Consequently, we show that ICP0 is able to overcome the HDAC5 amino-terminal- and MITR-induced MEF2A repression in gene reporter assays. This is the first report of a viral protein interacting with and controlling the repressor activity of class II HDACs. We discuss the putative consequences of such an interaction for the biology of the virus both during lytic infection and reactivation from latency.

Biphasic temporal pattern in exercise capacity after myocardial infarction in the rat: relationship to left ventricular remodeling

2005 ◽  
Vol 288 (1) ◽  
pp. H244-H249 ◽  
Author(s):  
Nathan A. Trueblood ◽  
Patrick R. Inscore ◽  
Daniel Brenner ◽  
Daniel Lugassy ◽  
Carl S. Apstein ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Exercise Capacity ◽  
Time Course ◽  
Ventricular Remodeling ◽  
Contractile Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Early Recovery ◽  
Functional Changes ◽  
Lv Remodeling

After myocardial infarction (MI), there is progressive left ventricular (LV) remodeling and impaired exercise capacity. We tested the hypothesis that LV remodeling results in structural and functional changes that determine exercise impairment post-MI. Rats underwent coronary artery ligation ( n = 12) or sham ( n = 11) surgery followed by serial exercise tests and echocardiography for 16 wk post-MI. LV pressure-volume relationships were determined using a blood-perfused Langendorff preparation. Exercise capacity was 60% of shams immediately post-MI ( P < 0.05) followed by a recovery to near normal during weeks 5– 8. Thereafter, there was a progressive decline in exercise capacity to ±40% of shams ( P < 0.01). At both 8 and 16 wk post-MI, fractional shortening (FS) was reduced and end-diastolic diameter (EDD) was increased ( P < 0.01). However, neither FS nor EDD correlated with exercise at 8 or 16 wk ( r2 < 0.12, P > 0.30). LV septal wall thickness was increased at both 8 ( P = 0.17 vs. shams) and 16 wk ( P = 0.035 vs. shams) post-MI and correlated with exercise at both times ( r2 ≥ 0.50 and P ≤ 0.02 at 8 and 16 wk). Neither end-diastolic volume nor maximum LV developed pressure at 16 wk correlated with exercise capacity. Exercise capacity follows a biphasic time course post-MI. An immediate decrease is followed by an early recovery phase that is associated with compensatory LV hypertrophy. Subsequently, there is a progressive decrease in exercise capacity that is independent of further changes in LV volume or contractile function.

Losartan prevents contractile dysfunction in rat myocardium after left ventricular myocardial infarction

2001 ◽  
Vol 281 (5) ◽  
pp. H2150-H2158 ◽  
Author(s):  
Marcel C. G. Daniëls ◽  
Rebecca S. Keller ◽  
Pieter P. de Tombe
Keyword(s):  
Myocardial Infarction ◽  
Sarcomere Length ◽  
Contractile Function ◽  
Left Ventricular ◽  
Contractile Dysfunction ◽  
Treatment Results ◽  
Twitch Force ◽  
Rat Hearts ◽  
Myofilament Function ◽  
Active Peak

We studied the effects of chronic losartan (Los) treatment on contractile function of isolated right ventricular (RV) trabeculae from rat hearts 12 wk after left ventricular (LV) myocardial infarction (MI) had been induced by ligation of the left anterior descending artery at 4 wk of age. After recovery, one-half of the animals were started on Los treatment (MI+Los; 30 mg · kg−1 · day−1per os); the remaining animals were not treated (MI group). Rats without infarction or Los treatment served as controls (Con group). MI resulted in increases in LV and RV weight and unstressed LV cavity diameter; these were partially prevented by Los treatment. The active peak twitch force-sarcomere length relation was depressed in MI compared with either Con or MI+Los. Likewise, maximum Ca2+saturated twitch force was depressed in MI, whereas twitch relaxation and twitch duration were prolonged. Myofilament function, as measured in skinned trabeculae, was not significantly different among the Con, MI, and MI+Los groups. We conclude that Los prevents contractile dysfunction in rat RV trabeculae after LV MI. Our results suggest that the beneficiary effect of Los treatment results not from improved myofilament function but rather from improved myocyte Ca2+homeostasis.

scholarly journals Inhibition of class I histone deacetylase activity represses matrix metalloproteinase-2 and -9 expression and preserves LV function postmyocardial infarction

2015 ◽  
Vol 308 (11) ◽  
pp. H1391-H1401 ◽  
Author(s):  
Santhosh K. Mani ◽  
Christine B. Kern ◽  
Denise Kimbrough ◽  
Benjamin Addy ◽  
Harinath Kasiganesan ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Left Ventricular ◽  
Class I ◽  
Matrix Metalloproteinase 2 ◽  
Lv Function ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Lv Remodeling

Left ventricular (LV) remodeling, after myocardial infarction (MI), can result in LV dilation and LV pump dysfunction. Post-MI induction of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, have been implicated as causing deleterious effects on LV and extracellular matrix remodeling in the MI region and within the initially unaffected remote zone. Histone deacetylases (HDACs) are a class of enzymes that affect the transcriptional regulation of genes during pathological conditions. We assessed the efficacy of both class I/IIb- and class I-selective HDAC inhibitors on MMP-2 and MMP-9 abundance and determined if treatment resulted in the attenuation of adverse LV and extracellular matrix remodeling and improved LV pump function post-MI. MI was surgically induced in MMP-9 promoter reporter mice and randomized for treatment with a class I/IIb HDAC inhibitor for 7 days post-MI. After MI, LV dilation, LV pump dysfunction, and activation of the MMP-9 gene promoter were significantly attenuated in mice treated with either the class I/IIb HDAC inhibitor tichostatin A or suberanilohydroxamic acid (voronistat) compared with MI-only mice. Immunohistological staining and zymographic levels of MMP-2 and MMP-9 were reduced with either tichostatin A or suberanilohydroxamic acid treatment. Class I HDAC activity was dramatically increased post-MI. Treatment with the selective class I HDAC inhibitor PD-106 reduced post-MI levels of both MMP-2 and MMP-9 and attenuated LV dilation and LV pump dysfunction post-MI, similar to class I/IIb HDAC inhibition. Taken together, these unique findings demonstrate that selective inhibition of class I HDACs may provide a novel therapeutic means to attenuate adverse LV remodeling post-MI.

Abstract 405: Inhibition of Class I Histone Deacetylases at Reperfusion Attenuates Ischemia-reperfusion Injury and Modifies Mitochondrial Acetylation

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Daniel J Herr ◽  
Sverre E Aune ◽  
Donald R Menick
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Class I ◽  
Mass Spectrometry Analysis ◽  
Rate Pressure Product ◽  
Lv Function ◽  
Mitochondrial Enzymes ◽  
Reperfusion Phase

Although rapid reperfusion of ischemic tissue is the treatment of choice for myocardial infarction, much of the resultant damage occurs as a consequence of reperfusion itself. Previously, we have shown that pretreatment with MS-275, a selective class I histone deacetylase (HDAC) inhibitor, preserves left-ventricular (LV) function and substantially reduces the area of infarcted tissue in isolated rat hearts subjected to ischemia-reperfusion (IR) injury. Here, we tested the hypothesis that MS-275 treatment at reperfusion reduces LV tissue damage and improves post-ischemic LV contractile function. To do this, hearts from male Sprague-Dawley rats were isolated and perfused ex vivo on a Langendorff perfusion apparatus. A saline-filled balloon was inserted into the left ventricle of the heart to monitor ventricular pressure development throughout the experiment. Hearts were subjected to 30 minutes of ischemia, followed by 60 minutes of reperfusion. MS-275 was administered during the entire reperfusion phase, and resultant functional data were compared to untreated hearts. There was no difference in any metric of pre-ischemic contractile function between groups. 10nM MS-275 administered at reperfusion significantly improved multiple measures of LV function, including dP/dtmax, -dP/dtmax, developed pressure and rate pressure product. We also observed a significant reduction in infarct area of treated hearts compared to control, as measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Unexpectedly, mass spectrometry analysis revealed significant changes in acetylation state of multiple mitochondrial enzymes. Administration of MS-275 during the reperfusion phase of IR is sufficient to partially rescue LV function from reperfusion-induced damage. This study emphasizes the importance of exploring class I HDAC inhibitors for protection against ischemia-reperfusion.

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