Combination of necroptosis and apoptosis inhibition enhances cardioprotection against myocardial ischemia-reperfusion injury.

Authors

Shizuka Koshinuma, Osaka Dental University, Osaka, JapanFollow
Masami Miyamae, Osaka Dental University, Osaka, JapanFollow
Kazuhiro Kaneda, Osaka Dental University, Osaka, JapanFollow
Junichiro Kotani, Osaka Dental University, Osaka, JapanFollow
Vincent M. Figueredo, Einstein Medical Center and Jefferson Medical CollegeFollow

Document Type

Article

Publication Date

10-11-2013

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Journal of Anesthesia.

October 11, 2013.

The published version is available at PMID: 24113863. Copyright © Springer

Abstract

PURPOSE: Necroptosis has been proposed as a mode of cell death that is a caspase-independent programmed necrosis. We investigated whether necroptosis is involved in myocardial ischemia-reperfusion injury in isolated guinea pig hearts and, if so, whether simultaneous inhibition of necroptosis and apoptosis confers enhanced cardioprotection.

METHODS: Isolated perfused guinea pig hearts were subjected to 30 min ischemia and 4 h reperfusion (control = CTL, n = 8). Necrostatin-1 (necroptosis inhibitor, 10 μM), Z-VAD (apoptosis inhibitor, 0.1 μM) and both inhibitors were administered starting 5 min before ischemia and during the initial 30 min of reperfusion (Nec, Z-VAD, Nec + Z-VAD; n = 8 each). Contractile recovery was monitored by left ventricular developed (LVDP) and end-diastolic (LVEDP) pressure. Infarct size was determined by triphenyltetrazolium chloride staining. Tissue samples were obtained after 4 h reperfusion to determine expression of receptor-interacting protein 1 (RIP1) and activated caspase 3 by Western blot analysis.

RESULTS: After reperfusion, Nec + Z-VAD had higher LVDP and lower LVEDP compared with CTL. Infarct size was reduced in Nec and Z-VAD compared with CTL. Combination of necroptosis and apoptosis inhibition further reduced infarct size. Expression of activated caspase 3 was not increased in Z-VAD and Nec + Z-VAD compared with Nec and CTL. Expression of RIP1 was preserved in Z-VAD and Nec + Z-VAD compared with CTL, suggesting RIP1-mediated necrosis is involved in myocardial ischemia-reperfusion injury.

CONCLUSION: Necroptosis is involved in myocardial ischemia-reperfusion injury, and simultaneous inhibition of necroptosis and apoptosis enhances the cardioprotective effect. These findings may provide a novel, additive strategy for cardioprotection in acute myocardial infarction.

Recommended Citation

Koshinuma, Shizuka; Miyamae, Masami; Kaneda, Kazuhiro; Kotani, Junichiro; and Figueredo, Vincent M., "Combination of necroptosis and apoptosis inhibition enhances cardioprotection against myocardial ischemia-reperfusion injury." (2013). Division of Cardiology Faculty Papers. Paper 31.
https://jdc.jefferson.edu/cardiologyfp/31

PubMed ID

24113863