title: First molecular evidence that inositol trisphosphate signaling contributes to infarct size reduction with preconditioning.
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.
authors.affiliation: Dept. of Emergency Medicine, Univ. of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655, USA. karin.przyklenk@umassmed.edu
authors.forename: Karin
authors.initials: K
authors.lastname: Przyklenk
authors.forename: Michelle
authors.initials: M
authors.lastname: Maynard
authors.forename: Peter
authors.initials: P
authors.lastname: Whittaker
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D003981:Diazoxide / Q000494:pharmacology; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology / Q000502:physiology*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009203:Myocardial Infarction / Q000209:etiology* / Q000473:pathology* / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; C025389:Itpr1 protein, mouse; D008562:Membrane Glycoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C; D003981:Diazoxide