Received January 23, 2008
Revised February 14, 2008
Accepted after revision February 14, 2008
Heart/Cardiac Muscle [240]
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The action of nitric oxide to enhance cell survival is mediated through a cGMP and ERK 1,2 pathway while p38 mitogen activated protein kinase dependent pathways do not alter cell death
Simon W Rabkin 1*
Michael Y Tsang 1
1 University of British Columbia
* To whom correspondence should be addressed. E-mail: rabkin{at}interchange.ubc.ca.
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Abstract |
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The objective of this study was to determine whether the dual action of nitric oxide (NO) on cardiomyocyte cell viability is mediated through p38 mitogen activated protein kinase (MAPK)-induced cell death and ERK 1,2 mediated cell survival pathways; and whether either of these is mediated through a cGMP/protein kinase G (PKG) pathway. Cell viability of cardiomyocytes from embryonic chick cardiomyocytes was assessed by the MTT assay, which is based on the ability of viable cells to reduce MTT. The NO donor sodium nitroprusside (SNP) produced a significant (p<0.01) concentration dependent reduction in cell viability or increase in cell death. SNP induced ERK1,2 phosphorylation and the MEK1,2 inhibitor PD 98059 significantly increased cell death. In contrast, SB202190, a relatively selective inhibitor of p38 MAPK, did not affect SNP-induced cell death. The cardioprotective effect of NO was likely mediated, in part through cGMP as ODQ a selective inhibitor of NO-sensitive guanylyl cyclase produced a significant enhancement of SNP-induced cell death. In contrast, the PKG inhibitor KT 5823 did not affect cell viability. In summary, these data suggest that NO through stimulation of soluble guanylyl cyclase activates MEK1,2 whose products ERK1,2 protects against cell death. In contrast, SNP-induced p38 MAPK activation does not modulate NO-induced cardiomyocyte cell death. Not all cGMP targets affect NO-induced cell death as the PKG pathway does not enhance or suppress NO-induced cardiomyocyte cell death. Enhancement of the ERK1,2 responses to NO may permit the beneficial effects of NO to predominate.
Key Words:
Cell signalling, Heart, Nitric oxide
