Abstract 12081: Atrial Fibrillation and Diastolic Dysfunction in Transgenic Mice Expressing Phosphorylation-Defective Mutant Sarcolipin
Sarcolipin (SLN), a major regulator of cardiac sarcoplasmic reticulum Ca2+ ATPase (SERCA), mediates the beta-adrenergic responses in atria. Recent studies have suggested that threonine 5 (T5) can modulate SLN function via phosphorylation/dephosphorylation mechanisms. To define the in vivo role of T5 phosphorylation on SLN function, we have generated a transgenic mouse model with cardiac-specific expression of gain-of-function mutant SLN (T5 to Alanine; T5A). Transgenic (TG) overexpression of mutant SLN maximally (∼90%) replaced the endogenous SLN protein in atria without altering the total SLN content. TG mice showed bi-atrial enlargement without ventricular hypertrophy. ECG recordings showed notched-P waves in 1-month-old TG mice, whereas in 6-months-old TG mice, the P waves were completely replaced with small F waves indicating atrial fibrillation (AF). Histopathological analyses showed myocyte disarray and fibrosis in the TG mice atria. Doppler echocardiographic analyses of TG mice showed enlarged left atria (LA diameter: WT-1.9±0.1 mm vs. TG-3.5±.4 mm; p<0.005), decreased ”A” velocity, increased transmitral flow velocity during early diastole (E) and decreased left atrial contraction ratio (TVIA/(VTIE+VTIA); WT-0.4±0.05 vs. TG-0.2±0.03; p<0.01). These results indicate that the expression of T5A mutant SLN results in atrial dilatation and dysfunction. Echocardiographic measurements show enhanced systolic function of the TG heart. The hemodynamic measurements, however showed increased LV end diastolic pressure (WT-3±1 mmHg vs. TG-11±1 mmHg; p<0.005), indicating the decreased diastolic function. Together, our data demonstrate that the chronic inhibition of SERCA pump by phosphorylation-defective mutant SLN results in AF and diastolic dysfunction.
- © 2010 by American Heart Association, Inc.