Cardiac Fatty Acid Binding Protein (FABP3) Depletes SR Calcium Load in Ventricular Myocytes

Abstract

Rationale: Cardiac fatty acid-binding protein (FABP3) is a cardiac-specific member of lipid-binding protein family and its expression level is often reduced in patients with diabetic heart diseases. Recent evidence suggests that FABP3 suppresses calcium transient and shortening of isolated rat cardiomyocytes. However, the underlying mechanisms are largely elusive. Objective: To determine the role of FABP3 in regulating SR calcium release. Results: In STZ-induced type I diabetes mouse model (DM), protein expression level of FABP3 was elevated, cardiac function was reduced and negatively correlated with FABP3 expression level. Amplitudes of cell shortening and calcium transient are both impaired in DM cardiomyocytes, which can be mimicked by applying FABP3 at pathological concentration to control cardiomyocytes. FABP3 reduces calcium transient amplitude of cardiomyocytes in a dose dependent manner (EC50 = 0.052 nmol/L). SR calcium content is reduced in DM cardiomyocytes and FABP3 depletes SR calcium content in cardiomyocytes. FABP3 colocalizes with SERCA, inhibits SERCA activity with a greater EC50 (0.49 nmol/L). Co-immunoprecipitation study suggests elevated FABP3 promotes binding between SERCA and phospholamban. FABP3 also colocalizes with RyR2, binds to RyR2 and promotes RyR2-mediated SR calcium leak. Conclusion: Increased FABP3 expression level in DM mice compromises cardiac function by reducing SR calcium load via two independent approaches: (A) to reduce SERCA activity by promoting PLB-SERCA interaction and (B) to enhance RyR2-mediated SR calcium leak.