Title

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

UMMS Affiliation

Department of Emergency Medicine; Department of Anesthesiology

Publication Date

5-30-2006

Document Type

Article

Subjects

Animals; Calcium Channels; Diazoxide; Gene Expression Regulation; Heart Ventricles; Inositol 1,4,5-Trisphosphate; *Ischemic Preconditioning, Myocardial; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Myocardial Infarction; Myocardium; Protein Kinase C; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Vasodilator Agents

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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)P(3)], the second messenger generated in parallel with the diacylglycerol-PKC pathway, remains poorly understood. We hypothesized that, if Ins(1,4,5)P(3) signaling [i.e., release of Ins(1,4,5)P(3) and subsequent binding to Ins(1,4,5)P(3) 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)P(3) 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)P(3) 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)P(3) [sodium salt of native Ins(1,4,5)P(3)], 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)P(3), 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)P(3) limited infarct size (52-58% vs. 56% of the LV in mutant controls). These data provide novel evidence that Ins(1,4,5)P(3) signaling contributes to infarct size reduction with PC.

Rights and Permissions

Citation: Am J Physiol Heart Circ Physiol. 2006 Oct;291(4):H2008-12. Epub 2006 May 26. Link to article on publisher's site

DOI of Published Version

10.1152/ajpheart.00313.2006

Related Resources

Link to article in PubMed

Journal/Book/Conference Title

American journal of physiology. Heart and circulatory physiology

PubMed ID

16731645