Transgenic overexpression of the sarcoplasmic reticulum Ca2+ATPase improves reticular Ca2+ handling in normal and diabetic rat hearts.
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 beta-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.
Vetter
Roland
R
Department of Toxicology, Institute of Clinical Pharmacology and Toxicology, Benjamin Franklin Medical Center, Freie Universität Berlin, D-14195 Berlin, Germany. rvetter@zedat.fu-berlin.de
Rehfeld
Uwe
U
Reissfelder
Christoph
C
Weiss
Wolfgang
W
Wagner
Kay-Dietrich
KD
Günther
Joachim
J
Hammes
Annette
A
Tschöpe
Carsten
C
Dillmann
Wolfgang
W
Paul
Martin
M
D000818:Animals; D030801:Animals, Genetically Modified; D002118:Calcium / Q000493:pharmacokinetics*; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D006801:Humans; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
C506948:Atp2a2 protein, rat; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; D000252:Calcium-Transporting ATPases; D002118:Calcium