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.

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.

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 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.

Right ventricular contractile protein function in rats with left ventricular myocardial infarction

1996 ◽  
Vol 271 (1) ◽  
pp. H73-H79 ◽  
Author(s):  
P. P. De Tombe ◽  
T. Wannenburg ◽  
D. Fan ◽  
W. C. Little
Keyword(s):  
Myocardial Infarction ◽  
Protein Function ◽  
Sarcomere Length ◽  
Contractile Function ◽  
Left Ventricular ◽  
Pulmonary Congestion ◽  
Computer Feedback ◽  
Significant Depression ◽  
Chemical Permeabilization ◽  
The Right

We studied contractile function in cardiac trabeculae isolated from the right ventricles (RV) of rats with experimental heart failure (HF) induced by left ventricular (LV) myocardial infarction (24 wk post-MI; n = 6) and from sham-operated rats (n = 7). Sarcomere length (SL) was measured by laser diffraction techniques, and force (F) was measured by silicon strain gauge. SL was kept constant at all times by computer feedback control. HF was associated with marked LV dilation and pulmonary congestion. In intact, RV twitching trabeculae, HF was associated with a depression of the F-SL relation at extracellular Ca2+ concentration ([Ca2+]o) = 1.5 mM and a depression of the F-[Ca2+]o relation at SL = 2.0 microns. HF was also associated with a significant depression of the F-intracellular [Ca2+] relation at SL = 2.0 microns measured after chemical permeabilization of these RV trabeculae (skinned fibers). Our results suggest that reduced force development in this model of HF is due, in part, to depressed function of the contractile filaments.

scholarly journals Cardioinotropic Effects in Subchronic Intoxication of Rats with Lead and/or Cadmium Oxide Nanoparticles

2021 ◽  
Vol 22 (7) ◽  
pp. 3466
Author(s):  
Svetlana V. Klinova ◽  
Boris A. Katsnelson ◽  
Ilzira A. Minigalieva ◽  
Oksana P. Gerzen ◽  
Alexander A. Balakin ◽  
...  
Keyword(s):  
Cadmium Oxide ◽  
Male Rats ◽  
Sliding Velocity ◽  
Muscle Type ◽  
In Vitro Motility Assay ◽  
Thin Filaments ◽  
In Vitro Motility ◽  
Toxic Impact ◽  
Cdo Nanoparticles

Subchronic intoxication was induced in outbred male rats by repeated intraperitoneal injections with lead oxide (PbO) and/or cadmium oxide (CdO) nanoparticles (NPs) 3 times a week during 6 weeks for the purpose of examining its effects on the contractile characteristics of isolated right ventricle trabeculae and papillary muscles in isometric and afterload contractions. Isolated and combined intoxication with these NPs was observed to reduce the mechanical work produced by both types of myocardial preparation. Using the in vitro motility assay, we showed that the sliding velocity of regulated thin filaments drops under both isolated and combined intoxication with CdO–NP and PbO–NP. These results correlate with a shift in the expression of myosin heavy chain (MHC) isoforms towards slowly cycling β–MHC. The type of CdO–NP + PbO–NP combined cardiotoxicity depends on the effect of the toxic impact, the extent of this effect, the ratio of toxicant doses, and the degree of stretching of cardiomyocytes and muscle type studied. Some indices of combined Pb–NP and CdO–NP cardiotoxicity and general toxicity (genotoxicity included) became fully or partly normalized if intoxication developed against background administration of a bioprotective complex.

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 Facilitated Cross-Bridge Interactions with Thin Filaments by Familial Hypertrophic Cardiomyopathy Mutations inα-Tropomyosin

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Fang Wang ◽  
Nicolas M. Brunet ◽  
Justin R. Grubich ◽  
Ewa A. Bienkiewicz ◽  
Thomas M. Asbury ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Molecular Mechanisms ◽  
Helical Structure ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Maximum Speed ◽  
Sliding Speed ◽  
Thin Filaments ◽  
In Vitro Motility ◽  
Cardiac Sarcomeres

Familial hypertrophic cardiomyopathy (FHC) is a disease of cardiac sarcomeres. To identify molecular mechanisms underlying FHC pathology, functional and structural differences in three FHC-related mutations in recombinantα-Tm (V95A, D175N, and E180G) were characterized using both conventional and modified in vitro motility assays and circular dichroism spectroscopy. Mutant Tm's exhibited reducedα-helical structure and increased unordered structure. When thin filaments were fully occupied by regulatory proteins, little or no motion was detected at pCa 9, and maximum speed (pCa 5) was similar for all tropomyosins. Ca2+-responsiveness of filament sliding speed was increased either by increasedpCa50(V95A), reduced cooperativityn(D175N), or both (E180G). When temperature was increased, thin filaments with E180G exhibited dysregulation at temperatures ~10°C lower, and much closer to body temperature, than WT. When HMM density was reduced, thin filaments with D175N required fewer motors to initiate sliding or achieve maximum sliding speed.

Abstract P780: Myosin Light Chain Dephosphorylation by Ppp1r12c Promotes Atrial Hypocontractility in Atrial Fibrillation

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Francisco J Gonzalez-Gonzalez ◽  
Perike Srikanth ◽  
Andrielle E Capote ◽  
Alsina Katherina M ◽  
Benjamin Levin ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Molecular Mechanisms ◽  
Contractile Function ◽  
Right Atrial ◽  
Western Blots

Atrial fibrillation (AF) is the most common sustained arrhythmia, with an estimated prevalence in the U.S.of 6.1 million. AF increases the risk of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. We have recently identified protein phosphatase 1 subunit 12c (PPP1R12C) as a key molecule targeting myosin light-chain phosphorylation in AF. Objective: We hypothesize that the overexpression of PPP1R12C causes hypophosphorylation of atrial myosin light-chain 2 (MLC2a), thereby decreasing atrial contractility in AF. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluate the role of the PP1c-PPP1R12C interaction in MLC2a de-phosphorylation, we utilized Western blots, co-immunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A), PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, associated with a reduction in atrial contractility and an increase in AF inducibility. All these discoveries suggest that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

Abstract P458: Myosin Light Chain Dephosphorylation By Ppp1r12c Promotes Atrial Hypocontractility In Atrial Fibrillation

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Francisco J Gonzalez-Gonzalez ◽  
Srikanth Perike ◽  
Frederick Damen ◽  
Andrielle Capote ◽  
Katherina M Alsina ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Molecular Mechanisms ◽  
Contractile Function ◽  
Right Atrial ◽  
Western Blots

Introduction: Atrial fibrillation (AF), is the most common sustained arrhythmia, with an estimated prevalence in the U.S. of 2.7 million to 6.1 million and is predictive to increase to 12.1 million in 2030. AF increases the chances of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. Objective: The overexpression of PPP1R12C, causes hypophosphorylation of atrial myosin light chain 2 (MLC2a), decreasing atrial contractility. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluated the role of PP1c-PPP1R12C interaction in MLC2a de-phosphorylation we used Western blots, coimmunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A) PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The Overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, that cause a reduction in atrial contractility and increases AF inducibility. All these discoveries advocate that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

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