Cardiac Myosin Activator CK-1316719 Increases MyoFibril ATPase Activity and Myocyte Contractility in a Rat Model of Heart Failure

2006 ◽  
Vol 12 (6) ◽  
pp. S88
Author(s):  
Robert L. Anderson ◽  
Raja F. Kawas ◽  
Maria V. Pokrovskii ◽  
Guillermo Godinez ◽  
Kenneth H. Lee ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atpase Activity ◽  
Rat Model ◽  
Cardiac Myosin ◽  
Myocyte Contractility ◽  
Myofibril Atpase

scholarly journals Human hypertrophic cardiomyopathy mutation R712L suppresses the working stroke of cardiac myosin and can be rescued by omecamtiv mecarbil

2020 ◽  
Author(s):  
Aaron Snoberger ◽  
Bipasha Barua ◽  
Jennifer L. Atherton ◽  
Henry Shuman ◽  
Eva Forgacs ◽  
...  
Keyword(s):  
Heart Failure ◽  
Hypertrophic Cardiomyopathy ◽  
Atpase Activity ◽  
Single Molecule ◽  
Cardiac Failure ◽  
Flow Chamber ◽  
Severe Form ◽  
Gliding Motility ◽  
Cardiac Myosin ◽  
Omecamtiv Mecarbil

AbstractHypertrophic cardiomyopathies (HCMs) are the leading cause of acute cardiac failure in young individuals. Over 300 mutations throughout β-cardiac myosin, including in the motor domain, are associated with HCM. A β-cardiac myosin motor mutation (R712L) leads to a severe form of HCM. Actin-gliding motility of R712L-myosin is inhibited, despite near normal ATPase kinetics. By optical trapping, the working stroke of R712L-myosin was decreased 4-fold, but actin-attachment durations were normal. A prevalent hypothesis that HCM mutants are hypercontractile is thus not universal. R712 is adjacent to the binding site of the heart failure drug omecamtiv mecarbil (OM). OM suppresses the working stroke of normal β-cardiac myosin, but remarkably, OM rescues the R712L-myosin working stroke. Using a flow chamber to interrogate a single molecule during buffer exchange, we found OM rescue to be reversible. Thus, the R712L mutation uncouples lever arm rotation from ATPase activity and this inhibition is rescued by OM.

scholarly journals Myosin with hypertrophic cardiac mutation R712L has a decreased working stroke which is rescued by omecamtiv mecarbil

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Aaron Snoberger ◽  
Bipasha Barua ◽  
Jennifer L Atherton ◽  
Henry Shuman ◽  
Eva Forgacs ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atpase Activity ◽  
Binding Site ◽  
Single Molecule ◽  
Cardiac Failure ◽  
Flow Chamber ◽  
Severe Form ◽  
Gliding Motility ◽  
Cardiac Myosin ◽  
Omecamtiv Mecarbil

Hypertrophic cardiomyopathies (HCMs) are the leading cause of acute cardiac failure in young individuals. Over 300 mutations throughout β-cardiac myosin, including in the motor domain, are associated with HCM. A β-cardiac myosin motor mutation (R712L) leads to a severe form of HCM. Actin-gliding motility of R712L-myosin is inhibited, despite near-normal ATPase kinetics. By optical trapping, the working stroke of R712L-myosin was decreased 4-fold, but actin-attachment durations were normal. A prevalent hypothesis that HCM mutants are hypercontractile is thus not universal. R712 is adjacent to the binding site of the heart failure drug omecamtiv mecarbil (OM). OM suppresses the working stroke of normal β-cardiac myosin, but remarkably, OM rescues the R712L-myosin working stroke. Using a flow chamber to interrogate a single molecule during buffer exchange, we found OM rescue to be reversible. Thus, the R712L mutation uncouples lever arm rotation from ATPase activity and this inhibition is rescued by OM.

Abstract 14390: The Cardiac Myosin Inhibitor, Ck-3772271, Attenuates Cardiac Fibrosis and Diastolic Dysfunction in the Dahl/salt Sensitive Rat Model of Heart Failure With Preserved Ejection Fraction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Xihui Xu ◽  
Darren T Hwee ◽  
James J Hartman ◽  
Jingying Wang ◽  
Yangsong Wu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
Rat Model ◽  
Left Atrial ◽  
Cardiac Fibrosis ◽  
Preserved Ejection Fraction ◽  
Cardiac Myosin ◽  
Atrial Area

Introduction: Heart failure with preserved ejection fraction (HFpEF) is characterized by underlying contractile dysfunction and progressive myocardial fibrosis and stiffness. CK-3772271 (CK-271) is a novel small molecule cardiac myosin inhibitor that reduces cardiac myosin ATPase activity and reduces cardiac contractility in unloaded isolated cardiomyocytes in vitro and in healthy rats and dogs in vivo . The effect of chronic CK-271 treatment on cardiac function and morphology was evaluated in the Dahl/Salt Sensitive (DSS) rat hypertension model of HFpEF. Methods: DSS male rats were fed either a control low salt (LS, 0.3% NaCl) or high salt (HS, 4% NaCl) diet to induce a hypertension-driven HFpEF disease phenotype. 6 weeks after HS diet treatment, DSS rats were randomized into two sub-groups: continued HS diet or a HS diet formulated with CK-271 (100 ppm) for an additional 6 weeks. Body mass, systolic blood pressure, and cardiac function were measured longitudinally. After 12 weeks of HS treatment, hearts were collected to assess cardiac fibrosis. Results: HS diet treatment increased systolic blood pressure (LS:132.2 ± 4.7 mm Hg vs. HS: 163.5 ± 4.0 mm Hg, mean ± SEM, p< 0.001) and caused cardiac hypercontractility as evidenced by an increase in the end-systolic pressure-volume relationship (LS: 0.8 ± 0.17 vs. HS: 2.1 ± 0.46 mm Hg/ml). HS diet also increased isovolumic relaxation time (IVRT) (LS: 16.8 ± 0.6 vs. HS: 22.8 ± 0.6 ms, p<0.0001), left atrial area (LS: 30.3 ± 0.8 vs. HS: 42.5 ± 2.2 mm 2 , p<0.0001) and cardiac fibrosis (LS: 3.4 ± 0.4 vs. HS: 5.0 ± 0.6 %). 6 weeks of CK-271 treatment reduced fractional shortening (HS: 53.8 ± 1.4 vs. HS+CK-271: 42.7 ± 1.0 %, p<0.0001) and reduced HS diet-induced diastolic dysfunction, including IVRT (HS: 22.8 ± 0.6 vs. HS+CK-271: 19.5 ± 0.5 ms, p<0.0001) and left atrial area (HS: 42.5 ± 2.2 vs. HS+CK-271: 35.4 ± 0.8 mm 2 , p<0.0001). Furthermore CK-271 reduced the development of cardiac fibrosis (HS: 5.0 ± 0.6 vs. HS+CK-271: 3.5 ± 0.3 %, p<0.05) induced by HS diet. Conclusion: The small molecule cardiac myosin inhibitor, CK-3772271, attenuated the development of cardiac hypercontractility, diastolic dysfunction and fibrosis in the DSS rat model of HFpEF. Cardiac myosin inhibition may be a novel approach to mitigate the development of HFpEF.

653 Frusemide and mortality in a rat model of chronic heart failure

2007 ◽  
Vol 6 (1) ◽  
pp. 139-139
Author(s):  
J SPRINGER ◽  
S STRASSBURG ◽  
S PALUS ◽  
B BOCKMEYER ◽  
Y AKASHI ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Rat Model

Protective Effect of Swertiamarin on Myocardial Injury Through Activation of Nrf2/HO-1 Pathway in Heart Failure Model of Rats

2020 ◽  
Vol 18 (3) ◽  
pp. 260-265
Author(s):  
Xu Lin ◽  
Zheng Xiaojun ◽  
Lv Heng ◽  
Mo Yipeng ◽  
Tong Hong
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Ejection Fraction ◽  
Protective Effect ◽  
Infarct Size ◽  
Rat Model ◽  
Left Ventricular ◽  
Related Factor ◽  
Nuclear Factor ◽  
Internal Dimension

The purpose of this study was to evaluate the protective effect of swertiamarin on heart failure. To this end, a rat model of heart failure was established via left coronary artery ligation. Infarct size of heart tissues was determined using triphenyl tetrazolium chloride staining. Echocardiography was performed to evaluate cardiac function by the determination of ejection fraction, left ventricular internal dimension in diastole and left ventricular internal dimension in systole. The effect of swertiamarin on oxidative stress was evaluated via enzyme-linked immunosorbent assay. The mechanism was evaluated using western blot. Administration of swertiamarin reduced the infarct size of heart tissues in rat models with heart failure. Moreover, swertiamarin treatment ameliorated the cardiac function, increased ejection fraction and fractional shortening, decreased left ventricular internal dimension in diastole and left ventricular internal dimension in systole. Swertiamarin improved oxidative stress with reduced malondialdehyde, while increased superoxide dismutase, glutathione, and GSH peroxidase. Furthermore, nuclear-factor erythroid 2-related factor 2, heme oxygenase and NAD(P)H dehydrogenase (quinone 1) were elevated by swertiamarin treatment in heart tissues of rat model with heart failure. Swertiamarin alleviated heart failure through suppression of oxidative stress response via nuclear-factor erythroid 2-related factor 2/heme oxygenase-1 pathway providing a novel therapeutic strategy for heart failure.

scholarly journals Novel Therapeutic Targets in Heart Failure: The Phospholipase Cβ1b–Shank3 Interface

2015 ◽  
Vol 7 ◽  
pp. CMT.S18480
Author(s):  
Elizabeth A. Woodcock ◽  
David R. Grubb
Keyword(s):  
Heart Failure ◽  
Protein Kinase ◽  
Inotropic Agents ◽  
Specific Enzyme ◽  
Pump Performance ◽  
New Class ◽  
Promising Target ◽  
Protein Kinase Cα ◽  
Myocyte Contractility ◽  
Contractile Performance

Inotropic agents are often used to improve the contractile performance of the failing myocardium, but this is often at a cost of increased myocardial ischemia and arrhythmia. Myocyte contractility depends on the release of Ca2+ from the sarcoplasmic reticulum, and this Ca2+ is subject to regulation by the phosphorylation status of phospholamban (PLN). Many currently used inotropic agents function by increasing the phosphorylation of PLN, but these also heighten the risk of ischemia. Another approach is to reduce the dephosphorylation of PLN, which can be achieved by inhibiting pathways upstream or downstream of the protein kinase Cα. Phospholipase Cβ1b is responsible for activating protein kinase Cα, and its activity is substantially heightened in failing myocardium. We propose phospholipase Cβ1b, a cardiac-specific enzyme, as a promising target for the development of a new class of inotropic agents. By reversing changes that accompany the transition to heart failure, it may be possible to provide well-tolerated improvement in pump performance.

scholarly journals S ‐glutathiolation impairs phosphoregulation and function of cardiac myosin‐binding protein C in human heart failure

2016 ◽  
Vol 30 (5) ◽  
pp. 1849-1864 ◽  
Author(s):  
Konstantina Stathopoulou ◽  
Ilka Wittig ◽  
Juliana Heidler ◽  
Angelika Piasecki ◽  
Florian Richter ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protein C ◽  
Human Heart ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Human Heart Failure ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding ◽  
And Function

Impairment of endothelium dependent responses in a rat model of chronic heart failure: effects of an exercise training protocol

1992 ◽  
Vol 26 (7) ◽  
pp. 694-697 ◽  
Author(s):  
D C Lindsay ◽  
C Jiang ◽  
F Brunotte ◽  
S Adamopoulos ◽  
A J S Coats ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Exercise Training ◽  
Rat Model ◽  
Training Protocol
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