Abstract 2668: Loss of Sarcolipin is Associated With Structural and Electrical Remodeling of Atria
Sarcolipin (SLN) is a key regulator of SERCA pump in atria. Down regulation of SLN in the atria of patients with chronic atrial fibrillation (AF) and in animal models of pacing induced AF suggest that SLN levels could contribute to the altered Ca2+ homeostasis in AF. To determine the role of SLN in AF, we have generated a SLN null (sln−/−) mouse model. Ablation of SLN increases the sarcoplasmic reticulum Ca2+ content (as measured by 10 mM caffeine-induced Ca2+ transient) in atrial myocytes (F/F0: WT 4.85±0.19 vs. sln−/− 6.07±0.27, p<0.01) and twitch Ca2+ transient (WT 2.26±0.12 vs. sln−/− 3.07±0.22, p<0.01), with the same fractional release (WT 47.3±3.0% vs. sln−/− 50.9±3.4%). Electrophysiological analyses have shown prolongation of the action potential duration at 90% repolarization (APD90) and increased L-type Ca2+ current (sln−/− 5.1±0.5 vs. WT 2.8±0.3; pA/pF), and no change in outward K current in the sln−/− atrial myocytes. Replacement of Na+ with Li+ in the perfusate Tyrode’s solution suppressed the late plateau and decreased APD90 suggesting that the activation of forward mode of sodium-calcium exchanger (NCX) also attribute to the late plateau and prolongation of APD90 in sln−/− mice atrial myocytes. Further, the delayed afterdepolarization (DAD) and triggered activities were observed more frequently in sln−/− atrial myocytes. To determine the structural remodeling in sln−/− atria, we performed histopathological analyses and gene expression studies. Picro Sirius Red stained sections revealed increased collagen deposition in sln−/− atria indicating the interstitial fibrosis (WT 15.14±1.9% vs. sln−/− 29.1±0.8 %). Microarray and subsequent RT-PCR analyses showed the altered expression of genes associated with AF such as matrix metalloproteinase-MMP3, tissue inhibitors of metalloproteinases-TIMP4, cell cycle control proteins, cytokines-BMP5 and TGFβ3, ECM protein-connexin 40 and cathepsin K in sln−/− atria. Taken together, our data suggest that loss of SLN function could predispose atria to arrhythmias, possibly AF.