Overexpression of mitogen-activated protein kinase kinase 6 in the heart improves functional recovery from ischemia in vitro and protects against myocardial infarction in vivo

J Biol Chem. 2005 Jan 7;280(1):669-76. doi: 10.1074/jbc.M406690200. Epub 2004 Oct 18.

Abstract

The mitogen-activated protein kinases (MAPK) have been the subject of many studies to identify signaling pathways that promote cell survival or death. In cultured cardiac myocytes, p38 MAPK promotes cell survival or death depending on whether it is activated by mitogen-activated protein kinase kinase 6 (MKK6) or MKK3, respectively. The objectives of the current study were to examine the effects of MKK6-mediated p38 activation in the heart in vivo. Accordingly, we generated transgenic (TG) mice that overexpress wild type MKK6 in a cardiac-restricted manner. Although p38 was about 17-fold more active in TG than non-transgenic (NTG) mouse hearts, TG mouse hearts were morphologically and functionally similar to those of NTG littermates. However, upon transient ischemia followed by reperfusion, the MKK6 TG mouse hearts exhibited significantly better functional recovery and less injury than NTG mouse hearts. Because MKK6 increases levels of the protective small heat shock protein, alpha B-crystallin (alpha BC), in cultured cardiac myocytes, we examined alpha BC levels in the mouse hearts. The level of alpha BC was 2-fold higher in MKK6 TG than NTG mouse hearts. Moreover, ischemia followed by reperfusion induced a 6.4-fold increase in alpha BC levels in the mitochondrial fractions of TG mouse hearts but no increase in alpha BC levels in any of the other fractions analyzed. These alterations in alpha BC expression and localization suggest possible mechanisms of cardioprotection in MKK6 TG mouse hearts.

Publication types

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

MeSH terms

  • Animals
  • Enzyme Activation
  • Gene Expression Regulation, Enzymologic
  • Humans
  • In Vitro Techniques
  • MAP Kinase Kinase 3 / genetics
  • MAP Kinase Kinase 3 / metabolism
  • MAP Kinase Kinase 6 / biosynthesis*
  • MAP Kinase Kinase 6 / genetics
  • Mice
  • Mice, Transgenic
  • Myocardial Infarction / enzymology*
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / prevention & control
  • Myocardial Reperfusion Injury / enzymology*
  • Myocardial Reperfusion Injury / physiopathology
  • Organ Specificity
  • Recovery of Function
  • alpha-Crystallin B Chain / metabolism

Substances

  • alpha-Crystallin B Chain
  • MAP Kinase Kinase 3
  • MAP Kinase Kinase 6
  • MAP2K3 protein, human
  • MAP2K6 protein, human