Sarcolipin (SLN) is a key regulator of cardiac sarcoplasmic reticulum Ca2+ ATPase (SERCA) and plays a critical role in maintaining cardiac Ca2+ homeostasis and atrial �-adrenergic response. Previous studies have shown that threonine 5 at the N-terminus of SLN modulates its function and mediates �-adrenergic responses.1 To determine the importance of threonine 5 phosphorylation in modulating atrial SLN activity, we have generated a TG mouse model with cardiac specific expression of phosphorylation defective, gain-of-function mutant sarcolipin (SLNT5A). Transgenic expression of SLNT5A results in severe atrial structural remodeling accompanied by bi-atrial enlargement, slower AP propagation and diastolic dysfunction. To determine if the activity of ubiquitin-proteasome system (UPS) contributes to the atrial structural remodeling, we measured the UPS activity in atria and ventricles of TG mice. Our results show that the chymotrypsin-like activity of proteasomes was significantly increased in atria (p<0.001) and in the ventricles (p<0.05) of TG mice and was accompanied by increased protein expression of 20S and 19S subunits of UPS components. The amount of polyubiquitinated proteins was significantly increased in atria of SLNT5A TG mice. Gene expression analyses have shown altered expression of E2 and E3 components of UPS in the TG mice atria. Additionally, pharmacological inhibition of proteasome with epoxomicin restored atrial electrical conductivity in the TG mice by reversing structural remodeling of the atria. Together, our studies suggest that activation of UPS may contribute to the atrial structural remodeling and conduction defects in the SLNT5A TG mice. Our future studies will address if the activation of UPS contributes to structural remodeling in persistent atrial fibrillation (AF) in humans.1. Bhupathy P, Babu GJ, Ito M, Periasamy M. Threonine-5 at the N-terminus can modulate sarcolipin function in cardiac myocytes. J Mol Cell Cardiol 2009;47:723-729.

Role of ubiquitin proteasome system in atrial structural remodeling in sarcolipin T5A transgenic mice

248th National Meeting (2014)

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