HNO Enhances SERCA2a Activity and Cardiomyocyte Function by Promoting Redox-Dependent Phospholamban Oligomerization

Sivakumaran, Vidhya; Stanley, Brian A.; Tocchetti, Carlo G.; Ballin, Jeff D.; Caceres, Viviane; Zhou, Lufang; Keceli, Gizem; Rainer, Peter P.; Lee, Dong I.; Huke, Sabine; Ziolo, Mark T.; Kranias, Evangelia G.; Toscano, John P.; Wilson, Gerald M.; O’Rourke, Brian; Kass, David A.; Mahaney, James E.; Paolocci, Nazareno

doi:10.1089/ars.2012.5057

Cited by 72 publications

(70 citation statements)

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“…Thus it is not surprising that the TauTKO heart exhibits differences from other models of heart failure (no change in phospholamban and SERCA2 expression and reduced phospholamban phosphorylation), as taurine deficiency not only alters the activity of the protein kinases and protein phosphatases, but also modulates both [Ca 2ϩ ] i and the Ca 2ϩ dependence of the SR Ca 2ϩ ATPase. However, it is also possible that the activity of the SR Ca 2ϩ ATPase of the TauTKO heart might be altered by the oligomerization state of phospholamban (42).…”

Section: Discussionmentioning

confidence: 99%

Role of protein phosphorylation in excitation-contraction coupling in taurine deficient hearts

Ramila

Jong

Pastukh

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Section: Discussionmentioning

confidence: 99%

Role of protein phosphorylation in excitation-contraction coupling in taurine deficient hearts

Ramila

Jong

Pastukh

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…Unlike NO•, HNO is resistant to ROS scavenging, does not develop tolerance to its actions, and may target oxidized sGC. 9,12,19,44,45 HNO also has a unique ability to enhance LV function, 8,16,46,47 considered dependent on both sGC-independent and sGC-dependent mechanisms. …”

Section: -Nca Treatment Protects Against Diabetes Mellitus-induced Cmentioning

confidence: 99%

Chronic Administration of the Nitroxyl Donor 1-Nitrosocyclo Hexyl Acetate Limits Left Ventricular Diastolic Dysfunction in a Mouse Model of Diabetes Mellitus In Vivo

Cao

Wong

Rosli

et al. 2015

Circ: Heart Failure

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Background-Nitroxyl (HNO), a redox congener of nitric oxide (NO•), is a novel regulator of cardiovascular function, combining concomitant positive inotropic, lusitropic, and vasodilator properties. Moreover, HNO exhibits myocardial antihypertrophic and superoxide-suppressing actions. Despite these favorable actions, the impact of chronic HNO administration has yet to be reported in the context of cardiomyopathy. Diabetic cardiomyopathy is characterized by early diastolic dysfunction and adverse left ventricular (LV) structural remodeling, with LV superoxide generation playing a major causal role. We tested the hypothesis that the HNO donor 1-nitrosocyclohexylacetate (1-NCA) limits cardiomyocyte hypertrophy and LV diastolic dysfunction in a mouse model of diabetes mellitus in vivo. Methods and Results-Diabetes mellitus was induced in male FVB/N mice using streptozotocin. After 4 weeks, diabetic and nondiabetic mice were allocated to 1-NCA therapy (83 mg/kg per day IP) or vehicle and followed up for a further 4 weeks. Diabetes mellitus-induced LV diastolic dysfunction was evident on echocardiography-derived E and A wave velocities, E:A ratio, deceleration, and isovolumic relaxation times; LV systolic function was preserved. Increased LV cardiomyocyte size, hypertrophic and profibrotic gene expression, and upregulation of LV superoxide were also evident. These characteristics of diabetic cardiomyopathy were largely prevented by 1-NCA treatment. Selectivity of 1-NCA as an HNO donor was demonstrated by sensitivity of acute 1-NCA to L-cysteine but not to hydroxocobalamin in the normal rat heart ex vivo. Conclusions-Our studies provide the first evidence that HNO donors may represent a promising strategy for treatment of diabetic cardiomyopathy and implies therapeutic efficacy in settings of chronic heart failure. (Circ Heart Fail. 2015;8:572-581.

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“…For example, we have shown that RNS (specifically nitroxyl) modifies PLB cysteines to increase PLB pentamer formation, decreasing monomeric PLB (the form that inhibits SERCA2a) and resulting in a faster Ca 2+ transient decline (Sivakumaran et al 2013; Kohr et al 2010). …”

Section: Introductionmentioning

confidence: 99%

Tri-modal regulation of cardiac muscle relaxation; intracellular calcium decline, thin filament deactivation, and cross-bridge cycling kinetics

et al. 2014

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Cardiac muscle relaxation is an essential step in the cardiac cycle. Even when the contraction of the heart is normal and forceful, a relaxation phase that is too slow will limit proper filling of the ventricles. Relaxation is too often thought of as a mere passive process that follows contraction. However, many decades of advancements in our understanding of cardiac muscle relaxation have shown it is a highly complex and well-regulated process. In this review, we will discuss three distinct events that can limit the rate of cardiac muscle relaxation: the rate of intracellular calcium decline, the rate of thin-filament de-activation, and the rate of cross-bridge cycling. Each of these processes are directly impacted by a plethora of molecular events. In addition, these three processes interact with each other, further complicating our understanding of relaxation. Each of these processes is continuously modulated by the need to couple bodily oxygen demand to cardiac output by the major cardiac physiological regulators. Length-dependent activation, frequency-dependent activation, and β-adrenergic regulation all directly and indirectly modulate calcium decline, thin-filament deactivation, and cross-bridge kinetics. We hope to convey our conclusion that cardiac muscle relaxation is a process of intricate checks and balances, and should not be thought of as a single rate-limiting step that is regulated at a single protein level. Cardiac muscle relaxation is a system level property that requires fundamental integration of three governing systems: intracellular calcium decline, thin filament deactivation, and cross-bridge cycling kinetics.

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HNO Enhances SERCA2a Activity and Cardiomyocyte Function by Promoting Redox-Dependent Phospholamban Oligomerization

Cited by 72 publications

References 50 publications

Role of protein phosphorylation in excitation-contraction coupling in taurine deficient hearts

Role of protein phosphorylation in excitation-contraction coupling in taurine deficient hearts

Chronic Administration of the Nitroxyl Donor 1-Nitrosocyclo Hexyl Acetate Limits Left Ventricular Diastolic Dysfunction in a Mouse Model of Diabetes Mellitus In Vivo

Tri-modal regulation of cardiac muscle relaxation; intracellular calcium decline, thin filament deactivation, and cross-bridge cycling kinetics

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