Dataset Information

SERCA2a superinhibition by human phospholamban triggers electrical and structural remodeling in mouse hearts.

ABSTRACT: Phospholamban (PLN), the reversible inhibitor of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a), is a key regulator of myocyte Ca(2+) cycling with a significant role in heart failure. We previously showed that the single amino acid difference between human and mouse PLN results in increased inhibition of Ca(2+) cycling and cardiac remodeling and attenuated stress responses in transgenic mice expressing the human PLN (hPLN) in the null background. Here we dissect the molecular and electrophysiological processes triggered by the superinhibitory hPLN in the mouse. Using a multidisciplinary approach, we performed global gene expression analysis, electrophysiology, and mathematical simulations on hPLN mice. We identified significant changes in a series of Na(+) and K(+) homeostasis genes/proteins (including Kcnd2, Scn9a, Slc8a1) and ionic conductance (including L-type Ca(2+) current, Na(+)/Ca(2+) exchanger, transient outward K(+) current). Simulation analysis suggests that this electrical remodeling has a critical role in rescuing cardiac function by improving sarcoplasmic reticulum Ca(2+) load and overall Ca(2+) dynamics. Furthermore, multiple structural and transcription factor gene expression changes indicate an ongoing structural remodeling process, favoring hypertrophy and myogenesis while suppressing apoptosis and progression to heart failure. Our findings expand current understanding of the hPLN function and provide additional insights into the downstream implications of SERCA2a superinhibition in the mammalian heart.

SUBMITTER: Wang HS

PROVIDER: S-EPMC3092331 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

SERCA2a superinhibition by human phospholamban triggers electrical and structural remodeling in mouse hearts.

Wang Hong-Sheng HS Arvanitis Demetrios A DA Dong Min M Niklewski Paul J PJ Zhao Wen W Lam Chi Keung CK Kranias Evangelia G EG Sanoudou Despina D

Physiological genomics 20110125 7

Phospholamban (PLN), the reversible inhibitor of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a), is a key regulator of myocyte Ca(2+) cycling with a significant role in heart failure. We previously showed that the single amino acid difference between human and mouse PLN results in increased inhibition of Ca(2+) cycling and cardiac remodeling and attenuated stress responses in transgenic mice expressing the human PLN (hPLN) in the null background. Here we dissect the molecular and elect ...[more]

PMID: 21266500

Similar Datasets

Project description:Pathological left ventricular hypertrophy (LVH) is consistently associated with prolongation of the ventricular action potentials. A number of previous studies, employing various experimental models of hypertrophy, have revealed marked differences in the effects of hypertrophy on action potential duration (APD) between myocytes from endocardial and epicardial layers of the LV free wall. It is not known, however, whether pathological LVH is also accompanied by redistribution of APD among myocytes from the same layer in the LV free wall. In the experiments here, LV epicardial action potential remodeling was examined in a mouse model of decompensated LVH, produced by cardiac-restricted transgenic G?q overexpression. Confocal linescanning-based optical recordings of propagated action potentials from individual in situ cardiomyocytes across the outer layer of the anterior LV epicardium demonstrated spatially non-uniform action potential prolongation in transgenic hearts, giving rise to alterations in spatial dispersion of epicardial repolarization. Local density and distribution of anti-Cx43 mmune reactivity in G?q hearts were unchanged compared to wild-type hearts, suggesting preservation of intercellular coupling. Confocal microscopy also revealed heterogeneous disorganization of T-tubules in epicardial cardiomyocytes in situ. These data provide evidence of the existence of significant electrical and structural heterogeneity within the LV epicardial layer of hearts with transgenic G?q overexpression-induced hypertrophy, and further support the notion that a small portion of electrically well connected LV tissue can maintain dispersion of action potential duration through heterogeneity in the activities of sarcolemmal ionic currents that control repolarization. It remains to be examined whether other experimental models of pathological LVH, including pressure overload LVH, similarly exhibit alterations in T-tubule organization and/or dispersion of repolarization within distinct layers of LV myocardium.

Dataset Information

SERCA2a superinhibition by human phospholamban triggers electrical and structural remodeling in mouse hearts.

Publications

SERCA2a superinhibition by human phospholamban triggers electrical and structural remodeling in mouse hearts.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets