Cyclosporin A regulates sodium-calcium exchanger (NCX1) gene expression in vitro and cardiac hypertrophy in NCX1 transgenic mice.
The cardiac-specific sodium-calcium exchanger (NCX1) is a GATA-4 dependent gene that is upregulated during cardiac hypertrophy and heart failure. To date, lack of an appropriate inhibitor of NCX1 and embryonic lethality of NCX1 knockout mice have slowed investigation of the relation between NCX1 upregulation and cardiac hypertrophy. Recently, in vitro studies have shown that cyclosporin A (CSA), a calcineurin inhibitor, significantly downregulated expression of the hypertrophic genes atrial natriuretic factor and beta-myosin heavy chain and protected against cardiac hypertrophy and heart failure in calcineurin overexpressing mice. This suggested that CSA might play an important role in the treatment of hypertrophy and heart failure. In an in vitro model of cardiac hypertrophy, we showed that CSA is a potent inhibitor of NCX1 basal expression and NCX1 promoter activity. Female homozygous transgenic mice that overexpress NCX1 develop heart failure and die prematurely after two or more pregnancies. Others have demonstrated that pressure overloaded wild-type mice treated with CSA do not develop cardiac hypertrophy and downregulate expression of NCX1. We investigated the effect of CSA on NCX1 expression and transverse aortic constriction-induced cardiac hypertrophy in NCX1 overexpressing mice. We found that CSA blunted these responses.
Jordan
Maria C
MC
Department of Physiology, University of California, Los Angeles, Los Angeles, California 90095, USA.
Quednau
Beate D
BD
Roos
Kenneth P
KP
Ross
Robert S
RS
Philipson
Kenneth D
KD
Nicholas
Susanne B
SB
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D065095:Calcineurin Inhibitors; D006332:Cardiomegaly / Q000235:genetics*; D016572:Cyclosporine / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D018995:Myosin Heavy Chains / Q000235:genetics; D011401:Promoter Regions, Genetic; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D017384:Sequence Deletion; D019831:Sodium-Calcium Exchanger / Q000235:genetics*
D065095:Calcineurin Inhibitors; D011994:Recombinant Proteins; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D016572:Cyclosporine; D009320:Atrial Natriuretic Factor; D018995:Myosin Heavy Chains