Transgenic overexpression of the sarcoplasmic reticulum Ca ²⁺ ATPase improves reticular Ca ²⁺ handling in normal and diabetic rat hearts

Slowed relaxation in diabetic cardiomyopathy (CM) is partially related to diminished expression of the sarcoplasmic reticulum (SR) Ca 2+ ‐ATPase SERCA2a. To evaluate the impact of SERCA2a overexpression on SR Ca 2+ handling in diabetic CM, we 1) generated transgenic rats harboring a human cytomegalovirus enhancer/chicken β‐actin promotor‐controlled rat SERCA2 transgene (SERCA2‐TGR), 2) characterized their SR phenotype, and 3) examined whether transgene expression may rescue SR Ca 2+ transport in streptozotocin‐induced diabetes. The transgene was expressed in all heart chambers. Compared to wild‐type (WT) rats, a heterozygous line exhibited increased SERCA2 mRNA (1.5‐fold), SERCA2 protein (+26%) and SR Ca 2+ uptake (+37%). Phospholamban expression was not altered. In SERCA2‐TGR, contraction amplitude (+48%) and rates of contraction (+34%) and relaxation (+35%) of isolated papillary muscles (PM) were increased ( P <0.05 vs. WT, respectively); the lusitropic and inotropic responses of PM to forskolin were stronger than in WT. In diabetic myocardium with SR dysfunction, Ca 2+ uptake and SERCA2 protein of SERCA2‐TGR were 1.3‐fold higher ( P <0.05 vs. diabetic WT). Thus, a SERCA2 overexpression in rat heart improves Ca 2+ uptake, accelerates relaxation and compensates, in part, for depressed Ca 2+ uptake in diabetic CM. Therefore, SERCA2 expression might constitute an important therapeutic target to rescue cardiac SR Ca 2+ handling in diabetes.