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

Joshua J. Martindale, Jason A. Wall, Diana M. Martinez-Longoria, Prafulla Aryal, Howard A. Rockman, Yiru Guo, Roberto Bolli, Christopher C. Glembotski

Research output: Contribution to journalArticlepeer-review

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, αB-crystallin (αBC), in cultured cardiac myocytes, we examined αBC levels in the mouse hearts. The level of αBC was 2-fold higher in MKK6 TG than NTG mouse hearts. Moreover, ischemia followed by reperfusion induced a 6.4-fold increase in αBC levels in the mitochondrial fractions of TG mouse hearts but no increase in αBC levels in any of the other fractions analyzed. These alterations in αBC expression and localization suggest possible mechanisms of cardioprotection in MKK6 TG mouse hearts.

Original languageEnglish (US)
Pages (from-to)669-676
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number1
DOIs
StatePublished - Jan 7 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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