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Influences of Increased Expression of the Ca 2+ ATPase of the Sarcoplasmic Reticulum by a Transgenic Approach on Cardiac Contractility
Author(s) -
DILLMANN WOLFGANG H.
Publication year - 1998
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1998.tb08255.x
Subject(s) - phospholamban , endoplasmic reticulum , contractility , myocyte , medicine , endocrinology , contraction (grammar) , cardiac muscle , heart failure , biology , diastole , chemistry , microbiology and biotechnology , blood pressure
Congestive heart failure is a significant clinical problem and leads to abnormalities in Ca 2+ transients and to decreases in the level of the Ca 2+ ATPase of the sarcoplasmic reticulum according to reports to some investigators. The Ca 2+ ATPase of the sarcoplasmic reticulum (SERCA2) contributes in an important manner to diastolic Ca 2+ lowering and relaxation of the heart. To determine the contractile alterations resulting from increased SERCA2 expression, we generated transgenic mice overexpressing a rat SERCA2 transgene. In these mice, SERCA2 mRNA was increased 2.6‐fold, the relative synthesis rate of SERCA2 protein 1.8‐fold, and SERCA2 protein levels 1.2‐fold. Functional analysis of Ca 2+ handling and contractile parameters in isolated cardiac myocytes indicated that the intracellular Ca 2+ decline and myocyte relengthening were each accelerated by 22‐23%. In addition, studies in isolated papillary muscles showed that the time to half‐maximal post‐rest potentiation was significantly shorter, hinting at an increased Ca 2+ loading of the sarcoplasmic reticulum. Furthermore, in vivo cardiac functional studies demonstrated a significant accelerated contraction and relaxation in SERCA2 transgenic mice. We also cloned a SERCA2 transgene and mutants of the phospholamban gene into E1 deleted replication‐deficient human adenovirus 5 viral vectors and infected cardiac myocytes. In the cardiac myocytes, endogenous SERCA2 levels were decreased by PMA treatment. Infection of such myocytes with a SERCA2 expressing adenovirus could reconstitute the Ca 2+ transient, and augmented oxalate facilitated SERCA2 Ca 2+ uptake. In addition, phospholamban mutants with changes of basic to acidic amino acids in the cytoplasmic domain increased SERCA2 activity by 30‐35%. These findings, therefore, suggest that increased SERCA2 activity can be achieved by increasing SERCA2 levels or by expressing phospholamban mutants. Increased SERCA2 activity can lead to significant enhancements of Ca 2+ transients and myocardial contractility.