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First molecular evidence that inositol trisphosphate signaling contributes to infarct size reduction with preconditioning

Departments of ¹Emergency Medicine and ²Anesthesiology, University of Massachusetts Medical School, Worcester Massachusetts

Submitted 27 March 2006 ; accepted in final form 22 May 2006

Considerable attention has focused on the role of protein kinase C (PKC) in triggering the profound infarct-sparing effect of ischemic preconditioning (PC). In contrast, the involvement of inositol 1,4,5-trisphosphate [Ins(1,4,5)P₃], the second messenger generated in parallel with the diacylglycerol-PKC pathway, remains poorly understood. We hypothesized that, if Ins(1,4,5)P₃ signaling [i.e., release of Ins(1,4,5)P₃ and subsequent binding to Ins(1,4,5)P₃ receptors] contributes to PC-induced cardioprotection, then the reduction of infarct size achieved with PC would be attenuated in mice that are deficient in Ins(1,4,5)P₃ receptor protein. To test this concept, hearts were harvested from 1) B6C3Fe-a/a-Itpr-1^opt+/–/J mutants displaying reduced expression of Ins(1,4,5)P₃ receptor-1 protein, 2) Itpr-1^opt+/+ wild types from the colony, and 3) C57BL/6J mice. All hearts were buffer-perfused and randomized to receive two 5-min episodes of PC ischemia, pretreatment with D-myo-Ins(1,4,5)P₃ [sodium salt of native Ins(1,4,5)P₃], the mitochondrial ATP-sensitive K⁺ channel opener diazoxide, or no intervention (controls). After the treatment phase, all hearts underwent 30-min global ischemia followed by 2 h of reperfusion, and infarct size was delineated by tetrazolium staining. In both wild-type and C57BL/6J cohorts, area of necrosis in hearts that received PC, D-myo-Ins(1,4,5)P₃, and diazoxide averaged 28–35% of the total left ventricle (LV), significantly smaller than the values of 52–53% seen in controls (P < 0.05). In contrast, in Itpr-1^opt+/– mutants, protection was only seen with diazoxide: neither PC nor D-myo-Ins(1,4,5)P₃ limited infarct size (52–58% vs. 56% of the LV in mutant controls). These data provide novel evidence that Ins(1,4,5)P₃ signaling contributes to infarct size reduction with PC.

myocardial ischemia; myocardial infarction; signal transduction; inositol 1,4,5-trisphosphate