Cardiac ankyrin repeat protein is a novel marker of cardiac hypertrophy - Role of M-CAT element within the promoter

CARP, a cardiac doxorubicin (adriamycin)-responsive protein, has been ident ified as a nuclear protein whose expression is downregulated in response to doxorubicin. In the present study, we tested the hypothesis that CARP serv es as a reliable genetic marker of cardiac hypertrophy in vivo and in vitro . CARP expression was markedly increased in 3 distinct models of cardiac hy pertrophy in rats: constriction of abdominal aorta, spontaneously hypertens ive rats, and Dahl salt-sensitive rats. In addition, we found that CARP mRN A levels correlate very strongly with the brain natriuretic peptide mRNA le vels in Dahl rats. Transient transfection assays into primary cultures of n eonatal rat cardiac myocytes indicate that transcription from the CARP and brain natriuretic peptide promoters is stimulated by overexpression of p38 and Rac1, components of the stress-activated mitogen-activated protein kina se pathways. Mutation analysis and electrophoretic mobility shift assays in dicated that the M-CAT element can serve as a binding site for nuclear fact ors, and this element is important for the induction of CARP promoter activ ity by p38 and Rac1. Thus, our data suggest that M-CAT element is responsib le for the regulation of the CARP gene in response to the activation of str ess-responsive mitogen-activated protein kinase pathways. Moreover, given t hat activation of these pathways is associated with cardiac hypertrophy, we propose that CARP represents a novel genetic marker of cardiac hypertrophy .