Impaired left ventricular mechanical and energetic function in mice after cardiomyocyte-specific excision of Serca2

Abstract

Boardman NT, Aronsen JM, Louch WE, Sjaastad I, Willoch F, Christensen G, Sejersted O, Aasum E. Impaired left ventricular mechanical and energetic function in mice after cardiomyocyte-specific excision of Serca2. Am J Physiol Heart Circ Physiol 306: H1018 -H1024, 2014. First published January 31, 2014 doi:10.1152 doi:10. /ajpheart.00741.2013plasmic reticulum Ca 2ϩ -ATPase (SERCA)2 transports Ca 2ϩ from the cytosol into the sarcoplasmic reticulum of cardiomyocytes and is essential for maintaining myocardial Ca 2ϩ handling and thus the mechanical function of the heart. SERCA2 is a major ATP consumer in excitation-contraction coupling but is regarded to contribute to energetically efficient Ca 2ϩ handling in the cardiomyocyte. Previous studies using cardiomyocytespecific SERCA2 knockout (KO) mice have demonstrated that decreased SERCA2 activity reduces the Ca 2ϩ transient amplitude and induces compensatory Ca 2ϩ transport mechanisms that may lead to more inefficient Ca 2ϩ transport. In this study, we examined the relationship between left ventricular (LV) function and myocardial O2 consumption (MV O2) in ex vivo hearts from SERCA2 KO mice to directly measure how SERCA2 elimination influences mechanical and energetic features of the heart. Ex vivo hearts from SERCA2 KO hearts developed mechanical dysfunction at 4 wk and demonstrated virtually no working capacity at 7 wk. In accordance with the reported reduction in Ca 2ϩ transient amplitude in cardiomyocytes from SERCA2 KO mice, work-independent MV O2 was decreased due to a reduced energy cost of excitation-contraction coupling. As these hearts also showed a marked impairment in the efficiency of chemomechanical energy transduction (contractile efficiency, i.e, workdependent MV O2), hearts from SERCA2 KO mice were found to be mechanically inefficient. This ex vivo evaluation of mechanical and energetic function in hearts from SERCA2 KO mice brings together findings from previous experimental and mathematical modelingbased studies and demonstrates that reduced SERCA2 activity not only leads to mechanical dysfunction but also to energetic dysfunction. mechanical efficiency; myocardial oxygen consumption; contractile efficiency; pressure-volume area; mechanoenergetics RELAXATION OF THE MYOCARDIUM occurs as the cytosolic Ca 2ϩ concentration returns to its resting level primarily through Ca 2ϩ reuptake into the sarcoplasmic reticulum (SR) by sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA)2. Thus, SERCA2 is essential for maintaining myocardial Ca 2ϩ homeostasis and mechanical function of the heart. A reduction in the capacity or the absence of SERCA2 has been shown to lead to reduced force generation, delayed relaxation, and advanced onset of heart failure (3, 11, 27), whereas increased SERCA2 expression (transgenic mice and/or adenovirus-mediated overexpression) has been shown to increase cardiac function in the normal and failing heart (28, 39) as well as to protect against ischemiareperfusion (12, 31) and pressure overload (28,35).Myocardial SERCA2 activities are d...

Sarcoendoplasmic Reticulum Ca2+ ATPase. A Critical Target in Chlorine Inhalation–Induced Cardiotoxicity

“…Total ATP content of chlorineexposed rat hearts decreased in a timedependent fashion ( Figure 1D). SERCA plays an important role in chemomechanical energy transduction of the heart (14). Chlorine inhalation markedly (.…”

“…However, such studies in hearts of chlorine-exposed animals are unknown. SERCA plays an important role in chemomechanical energy transduction of the heart (14). By sequestering cytosolic calcium in the endoplasmic reticulum, SERCA further regulates important signaling mechanisms critical for normal cell function, growth, and survival.…”

Assessing Cardiac Metabolism

“…136,322 They have also at times provided surprising insights regarding previously unknown functions, 323 the existence of overlapping or redundant pathways, 324–326 or novel interactions between metabolic pathways and other aspects of cardiac function such as excitation-contraction coupling. 118,327 In addition to models in which specific metabolic enzymes or transporters are perturbed, genetic models have also provided important insights into regulatory pathways, with profound effects on metabolic pathways within the myocardium. Recent advances in gene therapy methods have also enabled acute changes leading to functional gain and loss of metabolic enzymes in otherwise naïve animal models.…”

Myocardial mitochondrial dysfunction in mice lacking adiponectin receptor 1

“…Interestingly, a recent study demonstrated that lack of sarcoendoplasmic reticulum Ca 2? -ATPase 2a (SERCA2a) in the heart reduced cardiac efficiency, since the increase in MVO 2 consumption for a given increase in cardiac work was higher than in control hearts [4]. Thus, an impairment in excitation-contraction coupling efficiency represents another possibility to increase MVO 2 , possibly independent of mitochondrial uncoupling, that should be investigated in this animal model in future studies.…”