Transgenic overexpression of the sarcoplasmic reticulum Ca2+ ATPase improves reticular Ca2+ handling in normal and diabetic rat hearts

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Abstract
Slowed relaxation in diabetic cardiomyopathy (CM) is partially related to diminished expression of the sarcoplasmic reticulum (SR) Ca2+‐ATPase SERCA2a. To evaluate the impact of SERCA2a overexpression on SR Ca2+ 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 Ca2+ 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 Ca2+ 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 (P2+ uptake and SERCA2 protein of SERCA2‐TGR were 1.3‐fold higher (P2+ uptake, accelerates relaxation and compensates, in part, for depressed Ca2+ uptake in diabetic CM. Therefore, SERCA2 expression might constitute an important therapeutic target to rescue cardiac SR Ca2+ handling in diabetes.
Funding Information
  • Freie Universität Berlin