Abstract 3471: Ablation Of Phospholamban And Sarcolipin Has A Deleterious Effect On SERCA Pump Activity And Cardiac Contractility

Abstract

Recent studies have been directed towards the potential therapeutic value of improving the sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA) function in the failing myocardium. Overexpression of SERCA pump or inhibiting the function of phospholamban (PLB) has been shown to improve the cardiac function in failing myocardium. Towards this goal, we enhanced the SERCA pump activity in both atria and ventricle by ablating its key regulators, PLB and sarcolipin (SLN). The homozygous double knockout (dKO) pups were delivered in Mendelian ratio and reached adulthood without any visible abnormalities. However, these mice develop cardiac hypertrophy. The heart weight to body weight ratio significantly increased in 3– 4 months old dKO mice (WT-3.08±0.11 vs. dKO-4.14±0.14) and is associated with enlargement of myocytes (WT-117±8 μm2 vs. dKO-166±10 μm2). Ablation of PLB and SLN did not affect the expression of major Ca2+ handling proteins including SERCA2a, calsequestrin, L-type Ca2+ channel and ryanodine receptor in both atria and ventricles. Echocardiographic measurements showed increased diastolic (WT-0.90±0.02 mm vs. dKO-1.26±0.07 mm) and systolic (WT-1.33±0.03 mm vs. dKO-1.68±0.08 mm) septal wall thicknesses and diastolic (WT-0.91±0.02 mm vs. dKO-1.15±0.07 mm) and systolic (WT-1.15±0.03 mm vs. dKO-1.35±0.07 mm) post wall thickness in 3– 4 months old dKO mice hearts. However, left ventricular end-diastolic dimension (LVEDD), LV end-systolic dimension and ejection fraction (EF, %: WT-0.73±0.12 vs. dKO-0.69±0.03) are not very different from wildtype indicating preserved contractile function in the dKO mice. Our studies therefore suggest that the enhanced Ca2+ sensitivity of cardiac SERCA pump can progressively lead to cardiac hypertrophy and may have a deleterious effect on cardiac function during pathological conditions.