Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic function.

Published

Journal Article

Calcineurin is a Ca(2+)/calmodulin-activated protein phosphatase that transduces hypertrophic stimuli to regulate transcriptional control of myocyte transformation. It is not known whether overexpression of MCIP1, a recently described endogenous inhibitor of calcineurin, impacts the hypertrophic response to pathophysiologically relevant pressure overload. Further, the functional consequences of calcineurin inhibition by MCIP1 under conditions of hemodynamic stress are unknown. Transgenic mice expressing a human cDNA encoding hMCIP1 in the myocardium were subjected to thoracic aortic banding. Transgenic mice and wild type littermates tolerated pressure overload equally well. Wild type mice developed left ventricular hypertrophy, but the hypertrophic response in transgenics was significantly blunted. An isoform of MCIP1 transcript was up-regulated by pressure stress, whereas MCIP2 transcript was not. Expression patterns of fetal genes were differentially regulated in banded MCIP1 hearts compared with wild type. Echocardiography performed at 3 weeks and 3 months revealed preservation of both left ventricular size and systolic function in banded MCIP1 mice despite the attenuated hypertrophic response. These data demonstrate attenuation of hypertrophic transformation when calcineurin is inhibited by MCIP1. Further, these data suggest that activation of hypertrophic marker genes may not be directly dependent on calcineurin activity. Finally, they demonstrate that ventricular performance is preserved despite attenuation of compensatory hypertrophy.

Full Text

Duke Authors

Cited Authors

  • Hill, JA; Rothermel, B; Yoo, K-D; Cabuay, B; Demetroulis, E; Weiss, RM; Kutschke, W; Bassel-Duby, R; Williams, RS

Published Date

  • March 22, 2002

Published In

Volume / Issue

  • 277 / 12

Start / End Page

  • 10251 - 10255

PubMed ID

  • 11786544

Pubmed Central ID

  • 11786544

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M110722200

Language

  • eng

Conference Location

  • United States