Ablation of sarcolipin results in atrial remodeling

Xie LH, Shanmugam M, Park JY, Zhao Z, Wen H, Tian B, Periasamy M, Babu GJ. Ablation of sarcolipin results in atrial remodeling. Am J Physiol Cell Physiol 302: C1762-C1771, 2012. First published April 11, 2012; doi:10.1152/ajpcell.00425.2011.-Sarcolipin (SLN) is a key regulator of sarco(endo)plasmic reticulum (SR) Ca2+-ATPase (SERCA), and its expression is altered in diseased atrial myocardium. To determine the precise role of SLN in atrial Ca2+ homeostasis, we developed a SLN knockout (sln-/-) mouse model and demonstrated that ablation of SLN enhances atrial SERCA pump activity. The present study is designed to determine the long-term effects of enhanced SERCA activity on atrial remodeling in the sln-/- mice. Calcium transient measurements show an increase in atrial SR Ca2+ load and twitch Ca2+ transients. Patch-clamping experiments demonstrate activation of the forward mode of sodium/calcium exchanger, increased L-type Ca2+ channel activity, and prolongation of action potential duration at 90% repolarization in the atrial myocytes of sln-/- mice. Spontaneous Ca2+ waves, delayed afterdepolarization, and triggered activities are frequent in the atrial myocytes of sln-/- mice. Furthermore, loss of SLN in atria is associated with increased interstitial fibrosis and altered expression of genes encoding collagen and other extracellular matrix proteins. Our results also show that the sln-/- mice are susceptible to atrial arrhythmias upon aging. Together, these findings indicate that ablation of SLN results in increased SERCA activity and SR Ca2+ load, which, in turn, could cause abnormal intracellular Ca2+ handling and atrial remodeling.