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1 Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA
* To whom correspondence should be addressed. E-mail: Muhammad.Ashraf{at}UC.Edu.
The opening of mitochondrial KATP (mitoKATP) channels has a significant role in delayed ischemic preconditioning and nitric oxide (NO) is well known trigger for its activation. However, the source of NO remains unknown. Phosphorylation of endothelial nitric oxide synthase (eNOS) increases NO production and reduces apoptosis through the Akt signaling pathway. To elucidate the Akt signaling pathway involved in the opening and antiapoptotic effect of mitoKATP channel during delayed pharmacological preconditioning, the mitoKATP channel opener, diazoxide (DE) (7µg/kg i.p) alone, or DE plus L-NAME (30µg/kg i.v.), an inhibitor of NOS, or wortmannin (WTN, 15 µg/kg i.v.), an inhibitor of PI3-kinase, was administered to wild-type (WT), or eNOS-/- mice during DE-treatment. Twenty-four hours later, hearts were isolated, and subjected to 40 min ischemia and 30 min reperfusion (I/R). The effect of DE and other interventions on hemodynamic, TUNEL-staining and biochemical changes during I/R was assessed in mouse hearts. Treatment with DE resulted in 2.2-fold increase in phosphorylation of Akt, and a significant increase in eNOS and iNOS proteins. Akt is upstream of NOS and mitoKATP channel as simultaneous pretreatment of WTN with DE abolished phosphorylation of Akt which was not affected by L-NAME and 5-HD. In hearts treated with DE, cardiac function was significantly improved after I/R and apoptosis was also significantly decreased. WTN abolished the anti-apoptotic effect of DE. Similarly, SMT, a specific iNOS inhibitor when given to eNOS-/- mice which were pretreated with DE completely abolished the beneficial effects of DE on reduction of apoptotic death. DE was partially effective in eNOS-/- mice against the ischemic injury. It is concluded that DE activates Akt through PI3-kinase signaling pathway and iNOS/eNOS is downstream of Akt.
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