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Articles in PresS, published online ahead of print April 4, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00002.2002
Submitted on January 3, 2002
Accepted on April 3, 2002
1 Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
2 Pfizer Global Research & Development, Groton, CT, USA
* To whom correspondence should be addressed. E-mail: ylwang{at}rics.bwh.harvard.edu.
Signaling through the protein phosphatase calcineurin may play a critical role in cardiac hypertrophy. The gene for Down Syndrome Critical Region-1 (DSCR1) encodes a protein that is an endogenous calcineurin inhibitor. This study was designed to test the hypothesis that DSCR1 is directly induced by biomechanical stimuli. Neonatal rat cardiac myocytes were exposed to biaxial cyclic mechanical strain; mechanical strain upregulated DSCR1 mRNA expression in a time and amplitude-dependent manner (3.4 ± 0.2 fold at 8% strain for 6 hr, n=11, P<0.01) and this induction was angiotensin II and endothelin I -independent. Biomechanical induction of DSCR1 mRNA was partially blocked by calcineurin inhibition with cyclosporine A (30 ± 5%, n=3, P<0.01). DSCR1 promoter-reporter experiments showed that mechanical strain induced DSCR1 promoter activity by 2.3 fold, and that this induction was completely inhibited by cyclosporin A. Furthermore, DSCR1 gene expression was increased in the left ventricles of mice with pressure-overload hypertrophy induced by transverse aortic banding. These data demonstrate that biomechanical strain directly induces gene expression for the calcineurin inhibitor DSCR1 in cardiac myocytes, indicating that mechanically induced DSCR1 may regulate the hypertrophic response to mechanical overload.
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