Pim-1 kinase antagonizes aspects of myocardial hypertrophy and compensation to pathological pressure overload

Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13889-94. doi: 10.1073/pnas.0709135105. Epub 2008 Sep 10.

Abstract

Pim-1 kinase exerts potent cardioprotective effects in the myocardium downstream of AKT, but the participation of Pim-1 in cardiac hypertrophy requires investigation. Cardiac-specific expression of Pim-1 (Pim-WT) or the dominant-negative mutant of Pim-1 (Pim-DN) in transgenic mice together with adenoviral-mediated overexpression of these Pim-1 constructs was used to delineate the role of Pim-1 in hypertrophy. Transgenic overexpression of Pim-1 protects mice from pressure-overload-induced hypertrophy relative to wild-type controls as evidenced by improved hemodynamic function, decreased apoptosis, increases in antihypertrophic proteins, smaller myocyte size, and inhibition of hypertrophic signaling after challenge. Similarly, Pim-1 overexpression in neonatal rat cardiomyocyte cultures inhibits hypertrophy induced by endothelin-1. On the cellular level, hearts of Pim-WT mice show enhanced incorporation of BrdU into myocytes and a hypercellular phenotype compared to wild-type controls after hypertrophic challenge. In comparison, transgenic overexpression of Pim-DN leads to dilated cardiomyopathy characterized by increased apoptosis, fibrosis, and severely depressed cardiac function. Furthermore, overexpression of Pim-DN leads to reduced contractility as evidenced by reduced Ca(2+) transient amplitude and decreased percentage of cell shortening in isolated myocytes. These data support a pivotal role for Pim-1 in modulation of hypertrophy by impacting responses on molecular, cellular, and organ levels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Aorta / enzymology
  • Apoptosis
  • Cardiomegaly / chemically induced
  • Cardiomegaly / enzymology*
  • Cardiomegaly / pathology*
  • Cardiomegaly / physiopathology
  • Cells, Cultured
  • Endothelin-1 / pharmacology
  • Fibrosis
  • Muscle Contraction
  • Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-pim-1 / genetics
  • Proto-Oncogene Proteins c-pim-1 / metabolism*
  • Rats

Substances

  • Endothelin-1
  • Proto-Oncogene Proteins c-pim-1