HNO Enhances SERCA2a Activity and Cardiomyocyte Function by Promoting Redox-Dependent Phospholamban Oligomerization
Year: 2013
Type: article
Abstract: AIMS: Nitroxyl (HNO) interacts with thiols to act as a redox-sensitive modulator of protein function. It enhances sarcoplasmic reticular Ca(2+) uptake and myofilament Ca(2+) sensitivity, improving cardiac contractility. This activity has led to clinical testing of HNO donors for heart failure. Here we tested whether HNO alters the inhibitory interaction between phospholamban (PLN) and the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) in a redox-dependent manner, improving Ca(2+) handling in isolated myocytes/hearts. RESULTS: Ventriculocytes, sarcoplasmic reticulum (SR) vesicles, and whole hearts were isolated from control (wildtype [WT]) or PLN knockout (pln(-/-)) mice. Compared to WT, pln(-/-) myocytes displayed enhanced resting sarcomere shortening, peak Ca(2+) transient, and blunted β-adrenergic responsiveness. HNO stimulated shortening, relaxation, and Ca(2+) transient in WT cardiomyocytes, and evoked positive inotropy/lusitropy in intact hearts. These changes were markedly blunted in pln(-/-) cells/hearts. HNO enhanced SR Ca(2+) uptake in WT but not pln(-/-) SR-vesicles. Spectroscopic studies in insect cell microsomes expressing SERCA2a±PLN showed that HNO increased Ca(2+)-dependent SERCA2a conformational flexibility but only when PLN was present. In cardiomyocytes, HNO achieved this effect by stabilizing PLN in an oligomeric disulfide bond-dependent configuration, decreasing the amount of free inhibitory monomeric PLN available. INNOVATION: HNO-dependent redox changes in myocyte PLN oligomerization relieve PLN inhibition of SERCA2a. CONCLUSIONS: PLN plays a central role in HNO-induced enhancement of SERCA2a activity, leading to increased inotropy/lusitropy in intact myocytes and hearts. PLN remains physically associated with SERCA2a; however, less monomeric PLN is available resulting in decreased inhibition of the enzyme. These findings offer new avenues to improve Ca(2+) handling in failing hearts.
Source: Antioxidants and Redox Signaling
Authors: Vidhya Sivakumaran, Brian A. Stanley, Carlo G. Tocchetti, Jeff D. Ballin, Viviane Caceres, Lufang Zhou, Gizem Keceli, Peter P. Rainer, Dong I. Lee, Sabine Huke, Mark T. Ziolo, Evangelia G. Kranias, John P. Toscano, Gerald M. Wilson, Brian O'Rourke, David A. Kass, James E. Mahaney, Nazareno Paolocci
Institutions: Johns Hopkins Medicine, Johns Hopkins Hospital, Virginia Tech, University of Maryland, Baltimore, Excet (United States), U.S. Army Combat Capabilities Development Command Chemical Biological Center, Universidade Federal de São Paulo, University of Alabama at Birmingham, Johns Hopkins University, Medical University of Graz, Vanderbilt University, The Ohio State University, University of Cincinnati, Edward Via College of Osteopathic Medicine, University of Perugia
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Mechanisms directing oncoprotein and cytokine mRNA decay, Pathobiology of Cardiac Dyssynchrony & Resynchronization, Nitric oxide signaling in healthy and diseased cardiac myocytes, Investigate the effect of mitochondrial energy state on Ca2+ sparks and handling, Calcium Handling in Cardiac Pathophysiology, Nitroxyl cardiac effects are mediated by cAMP/PKA signal, G5005330114, Mechanisms Underlying Mitrochondrial Dysfunction in the Diabetic Heart, MItochondrial Dysfunction in Cardiac Hypertrophy and Failure, Redox Modification of the Arrhythmic Substrate in Heart Failure, NOS1/NOS3 Functional Effects on Cardiac Myocyte Function, Calcium Pump Nitration and Inhibition of Calcium Transport in the Aging Heart, Cardiac Sarcoplasmic Reticulum Calcium Cycling Proteins
OpenAlex ID: W2007011272