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Updated: Aug 8, 2026
Histological Quantification of Chronic Myocardial Infarct in Rats
Published on: December 11, 2016
First molecular evidence that inositol trisphosphate signaling contributes to infarct size reduction with
Karin Przyklenk1, Michelle Maynard, Peter Whittaker
1Dept. of Emergency Medicine, Univ. of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655, USA. karin.przyklenk@umassmed.edu
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.
Insights
Inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) signaling is crucial for ischemic preconditioning (PC)-induced cardioprotection. Mice lacking Ins(1,4,5)P3 receptors showed no infarct size reduction with PC, highlighting the pathway's importance.
Area of Science:
- Cardiovascular Research
- Cell Signaling
- Molecular Cardiology
Background:
- Ischemic preconditioning (PC) protects the heart from infarction, with protein kinase C (PKC) implicated.
- The role of inositol 1,4,5-trisphosphate (Ins(1,4,5)P3), a parallel second messenger, in PC-induced cardioprotection is not well understood.
Purpose of the Study:
- To investigate the contribution of Ins(1,4,5)P3 signaling to PC-induced infarct size reduction.
- To test if Ins(1,4,5)P3 receptor deficiency attenuates the protective effects of PC.
Main Methods:
- Buffer-perfused hearts from wild-type and Ins(1,4,5)P3 receptor-deficient mice were subjected to PC or treated with Ins(1,4,5)P3 or diazoxide.
- Hearts underwent global ischemia and reperfusion, and infarct size was measured.
- Comparisons were made between PC, Ins(1,4,5)P3, diazoxide, and control groups.
Main Results:
- In wild-type hearts, PC, Ins(1,4,5)P3, and diazoxide significantly reduced infarct size (28-35% of LV) compared to controls (52-53%).
- In Ins(1,4,5)P3 receptor-deficient mice, only diazoxide provided protection; PC and Ins(1,4,5)P3 failed to limit infarct size (52-58% vs. 56% in controls).
Conclusions:
- These findings provide novel evidence that Ins(1,4,5)P3 signaling is essential for the infarct-limiting effects of ischemic preconditioning.
- Targeting the Ins(1,4,5)P3 pathway may offer therapeutic strategies for cardioprotection.
