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.
Highlights
The myocardium can be stressed by chronic increases in blood pressure, ischemia followed by reperfusion (I/R),1 or increases in neurohumoral substances, such as peptide hor
1 The abbreviations used are: I/R, ischemia followed by reperfusion; HSP, heat shock protein; TG, transgenic; NTG, non-transgenic; ERK, extracellular signal-regulated kinase; JNK, c-Jun NH2-terminal kinase; left ventricular developed pressure (LVDP), left ventricular (LV) developed pressure; ANOVA, analysis of variance; ␣BC, ␣B-crystallin; MKK, mitogen-activated protein kinase kinase; COX, cytochrome c oxidase
The effects of mitogen-activated protein kinase kinase 6 (MKK6) overexpression on mitogen-activated protein kinase activity were assessed focusing on p38␣ and -, the two major isoforms of this mitogen-activated protein kinase in the heart [22, 32, 33]
Summary
The myocardium can be stressed by chronic increases in blood pressure, ischemia followed by reperfusion (I/R), or increases in neurohumoral substances, such as peptide hor-. Numerous signals are activated in stressed cardiac myocytes; in some cases those signals mediate protection, whereas in others they mediate damage [1,2,3,4,5] Because of their potential to serve as targets for the development of therapies aimed at reducing the effects of stress on myocardial damage, the mitogen-activated protein kinases have been the focus of many recent studies. The isolated perfused heart model has been used to study roles for p38 in preconditioning and/or mediating the damage observed during I/R. Many of these studies demonstrated that p38 is activated during ischemia and/or reperfusion [14, 15]. There has been speculation on the reasons for these seemingly paradoxical results [8], in the isolated perfused heart I/R model it remains unclear whether p38 damages or protects
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