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Role of iNOS-derived reactive nitrogen species and resultant nitrative stress in leukocytes-induced cardiomyocyte apoptosis after myocardial ischemia/reperfusion

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Abstract

Polymorphonuclear leukocyte (PMN) accumulation/activation has been implicated as a primary mechanism underlying MI/R injury. Recent studies have demonstrated that PMNs express inducible nitric oxide synthase (iNOS) and produce toxic reactive nitrogen species (RNS). However, the role of iNOS-derived reactive nitrogen species and resultant nitrative stress in PMN-induced cardiomyocyte apoptosis after MI/R remains unclear. Male adult rats were subjected to 30 min of myocardial ischemia followed by 5 h of reperfusion. Animals were randomized to receive one of the following treatments: MI/R+vehicle; MI/R+L-arginine; PMN depletion followed by MI/R+vehicle; PMN depletion followed by MI/R+L-arginine; MI/R+1400 W; MI/R+1400 W+L-arginine and MI/R+ FeTMPyP. Ischemia/reperfusion-induced and L-arginine-enhanced nitrative stress and cardiomyocyte apoptosis were determined. PMN depletion virtually abolished ischemia/reperfusion- induced PMN accumulation, attenuated ischemic/reperfusion-induced and L-arginine-enhanced nitrative stress, and reduced ischemic/reperfusion-induced and L-arginine-enhanced cardiomyocyte apoptosis (P values all <0.01). Pre-treatment with 1400 W, a highly selective iNOS inhibitor, had no effect on PMN accumulation in the ischemic/reperfused tissue. However, this treatment reduced ischemia/reperfusion-induced and L-arginine-enhanced nitrative stress and cardiomyocyte apoptosis to an extent that is comparable as that seen in PMN depletion group. Treatment with FeTMPyP, a peroxynitrite decomposition catalyst, had no effect on either PMN accumulation or total NO production. However, treatment with this ONOO− decomposition catalyst also reduced ischemia/reperfusion-induced and L-arginine-enhanced nitrative stress and cardiomyocyte apoptosis (P values all <0.01). These results demonstrated that ischemic/reperfusion stimulated PMN accumulation may result in cardiomyocyte injury by an iNOS-derived nitric oxide initiated and peroxynitrite-mediated mechanism. Therapeutic interventions that block PMN accumulation, inhibit iNOS activity or scavenge peroxynitrite may reduce nitrative stress and attenuate tissue injury.

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Acknowledgment

This research was supported in part by NIH grant 2R01HL-63828, a research award from the American Diabetes Association (7-05-RA-83), a research award from the Commonwealth of Pennsylvania- Department of Health (to XLM), and NSFC 30572084 (to HRL).

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Authors and Affiliations

  1. Department of Physiology, Shanxi Medical University, 56 South Xinjian Road, Taiyuan, Shanxi, 030001, P.R. China

    Xiao-Liang Wang, Hui-Rong Liu, Li Yan & Rong-Rui Zhao

  2. Department of Emergency Medicine, Thomas Jefferson University, 1020 Sansom Street, Philadelphia, PA, 19107, USA

    Lin Tao, Bernard L. Lopez, Theodore A. Christopher & Xin-Liang Ma

  3. Department of Cardiothoracic Surgery, General Hospital of Taiyuan Iron and Steel Company, 23 Baiyangshu Street, Taiyuan, Shanxi, 030003, P.R. China

    Feng Liang

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  1. Xiao-Liang Wang
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Correspondence to Xin-Liang Ma.

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Xiao-Liang Wang and Hui-Rong Liu contributed equally to this study.

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Wang, XL., Liu, HR., Tao, L. et al. Role of iNOS-derived reactive nitrogen species and resultant nitrative stress in leukocytes-induced cardiomyocyte apoptosis after myocardial ischemia/reperfusion. Apoptosis 12, 1209–1217 (2007). https://doi.org/10.1007/s10495-007-0055-y

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