Background—Recently, we reported that sarcoplasmic reticulum Ca ATPase 2a (SERCA2a), the pump responsible for reuptake of cytosolic calcium during diastole, plays a central role in the molecular mechanism of cardiac alternans. Heart failure (HF) is associated with impaired myocardial calcium handling, deficient SERCA2a, and increased susceptibility to cardiac alternans. Therefore, we hypothesiz...

Background—In heart failure, sarcoplasmic reticulum (SR) Ca-ATPase (SERCA2a) activity is decreased, resulting in abnormal calcium handling and contractile dysfunction. We have previously shown that increasing SERCA2a expression by gene transfer improves ventricular function in a rat model of heart failure created by ascending aortic constriction. Methods and Results—In this study, we tested the...

BACKGROUND Low activity of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a) resulting from strong inhibition by phospholamban (PLN) can depress cardiac contractility and lead to dilated cardiomyopathy and heart failure. Here, we investigated whether PLN exhibits cardiotoxic effects via mechanisms other than chronic inhibition of SERCA2a by studying a PLN mutant, PLN(R9C), that triggers ...

Cardiac sarcoplasmic reticulum (SR) Ca2þ ATPase (SERCA2a) plays a central role in myocardial contractility. SERCA2a actively transports Ca2þ into the SR and regulates cytosolic Ca2þ concentration, SR Ca2þ load, and the rate of contraction and relaxation of the heart. In the heart, SERCA pump activity is regulated by two small molecular weight proteins: phospholamban (PLB) and sarcolipin (SLN). ...

Diastolic dysfunction results from impaired ventricular relaxation and is an important component of human heart failure. Genetic modification of intracellular calcium-handling proteins may hold promise to redress diastolic dysfunction; however, it is unclear whether other important aspects of myocyte function would be compromised by this approach. Accordingly, a large animal model of humanlike ...

OBJECTIVE To verify whether a deficiency in the cardiac sarcoplasmic reticulum pump SERCA2a causes cardiac dysfunction in humans. DESIGN Cardiac performance was measured in a serendipitous human model of primary SERCA2a deficiency, Darier's disease, an autosomal dominant skin disorder caused by mutations inactivating one copy of the ATP2A2 gene, which encodes SERCA2a. METHODS Systolic and d...

Heart failure is one of the leading causes of sudden death in developed countries. While current therapies are mostly aimed at mitigating associated symptoms, novel therapies targeting the subcellular mechanisms underlying heart failure are emerging. Failing hearts are characterized by reduced contractile properties caused by impaired Ca(2+) cycling between the sarcoplasm and sarcoplasmic retic...

Abnormal intracellular Ca(2+) cycling plays an important role in cardiac dysfunction and ventricular arrhythmias in the setting of heart failure and transient cardiac ischemia followed by reperfusion (I/R). We hypothesized that overexpression of the sarcoplasmic reticulum Ca(2+) ATPase pump (SERCA2a) may improve both contractile dysfunction and ventricular arrhythmias. Continuous ECG recordings...

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 sarcop...