RGD Reference Report - 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.

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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.
Authors:	Martindale, JJ Wall, JA Martinez-Longoria, DM Aryal, P Rockman, HA Guo, Y Bolli, R Glembotski, CC
Citation:	Martindale JJ, etal., J Biol Chem. 2005 Jan 7;280(1):669-76. Epub 2004 Oct 18.
RGD ID:	1582277
Pubmed:	PMID:15492008 (View Abstract at PubMed)
PMCID:	PMC3691679 (View Article at PubMed Central)
DOI:	DOI:10.1074/jbc.M406690200 (Journal Full-text)
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.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
MAP2K6	Human	Myocardial Reperfusion Injury		IMP			RGD
Map2k6	Rat	Myocardial Reperfusion Injury		ISO	MAP2K6 (Homo sapiens)		RGD
Map2k6	Mouse	Myocardial Reperfusion Injury		ISO	MAP2K6 (Homo sapiens)		RGD

Objects Annotated

Genes (Rattus norvegicus)

Map2k6 (mitogen-activated protein kinase kinase 6)

Genes (Mus musculus)

Map2k6 (mitogen-activated protein kinase kinase 6)

Genes (Homo sapiens)

MAP2K6 (mitogen-activated protein kinase kinase 6)

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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.