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Chronic beta-adrenergic receptor stimulation induces cardiac apoptosis and aggravates myocardial ischemia/reperfusion injury by provoking inducible nitric-oxide synthase-mediated nitrative stress.
J Pharmacol Exp Ther. 2006 Aug; 318(2):469-75.JP

Abstract

The present study provides evidence that inducible nitric-oxide synthase (iNOS)-mediated nitrative stress plays a pivotal role in chronic beta-adrenergic receptor (AR) stimulation-induced cardiac damage. In mice, 14 days of isoproterenol (ISO) stimulation via an osmotic minipump induced an up-regulation of iNOS as evidenced by increases in mRNA, protein expression, and immunochemical staining of myocardial iNOS. Serum level of C-reactive protein, an inflammatory mediator, was also markedly increased. Under chronic ISO stimulation, the up-regulated iNOS produced a significantly increased amount of nitric oxide (NO) and its byproduct, peroxynitrite, in the circulation and heart and subsequently resulted in an accelerated myocardial apoptosis. Forty-minute myocardial ischemia (MI) and 24-h reperfusion (R) further increased NO production and peroxynitrite formation and resulted in an enlarged infarct size in mice receiving chronic ISO stimulation. However, the treatment with a selective iNOS inhibitor [N-(3-(aminomethyl) benzyl)acetamidine] (1400W) or the use of a genetic modified animal (iNOS-knockout mice) markedly reduced iNOS-mediated production of NO and formation of peroxynitrite and consequently significantly decreased myocardial apoptosis and infarct size, showing a crucial link between iNOS-mediated nitrative stress and myocardial injury. In conclusion, chronic beta-AR stimulation up-regulates iNOS expression and increases NO production in the heart, which subsequently markedly enhances formation of reactive nitrogen species/peroxynitrite in the heart, thereby eliciting myocardial apoptosis and potentiating MI/R injury.

Authors+Show Affiliations

Department of Anesthesiology, Suite G8490, 111 South 11th Street, Philadelphia, PA 19107, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16574780

Citation

Hu, Aihua, et al. "Chronic Beta-adrenergic Receptor Stimulation Induces Cardiac Apoptosis and Aggravates Myocardial Ischemia/reperfusion Injury By Provoking Inducible Nitric-oxide Synthase-mediated Nitrative Stress." The Journal of Pharmacology and Experimental Therapeutics, vol. 318, no. 2, 2006, pp. 469-75.
Hu A, Jiao X, Gao E, et al. Chronic beta-adrenergic receptor stimulation induces cardiac apoptosis and aggravates myocardial ischemia/reperfusion injury by provoking inducible nitric-oxide synthase-mediated nitrative stress. J Pharmacol Exp Ther. 2006;318(2):469-75.
Hu, A., Jiao, X., Gao, E., Koch, W. J., Sharifi-Azad, S., Grunwald, Z., Ma, X. L., & Sun, J. Z. (2006). Chronic beta-adrenergic receptor stimulation induces cardiac apoptosis and aggravates myocardial ischemia/reperfusion injury by provoking inducible nitric-oxide synthase-mediated nitrative stress. The Journal of Pharmacology and Experimental Therapeutics, 318(2), 469-75.
Hu A, et al. Chronic Beta-adrenergic Receptor Stimulation Induces Cardiac Apoptosis and Aggravates Myocardial Ischemia/reperfusion Injury By Provoking Inducible Nitric-oxide Synthase-mediated Nitrative Stress. J Pharmacol Exp Ther. 2006;318(2):469-75. PubMed PMID: 16574780.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chronic beta-adrenergic receptor stimulation induces cardiac apoptosis and aggravates myocardial ischemia/reperfusion injury by provoking inducible nitric-oxide synthase-mediated nitrative stress. AU - Hu,Aihua, AU - Jiao,Xiangying, AU - Gao,Erhe, AU - Koch,Walter J, AU - Sharifi-Azad,Said, AU - Grunwald,Zvi, AU - Ma,Xin L, AU - Sun,Jian-Zhong, Y1 - 2006/03/30/ PY - 2006/4/1/pubmed PY - 2006/9/1/medline PY - 2006/4/1/entrez SP - 469 EP - 75 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 318 IS - 2 N2 - The present study provides evidence that inducible nitric-oxide synthase (iNOS)-mediated nitrative stress plays a pivotal role in chronic beta-adrenergic receptor (AR) stimulation-induced cardiac damage. In mice, 14 days of isoproterenol (ISO) stimulation via an osmotic minipump induced an up-regulation of iNOS as evidenced by increases in mRNA, protein expression, and immunochemical staining of myocardial iNOS. Serum level of C-reactive protein, an inflammatory mediator, was also markedly increased. Under chronic ISO stimulation, the up-regulated iNOS produced a significantly increased amount of nitric oxide (NO) and its byproduct, peroxynitrite, in the circulation and heart and subsequently resulted in an accelerated myocardial apoptosis. Forty-minute myocardial ischemia (MI) and 24-h reperfusion (R) further increased NO production and peroxynitrite formation and resulted in an enlarged infarct size in mice receiving chronic ISO stimulation. However, the treatment with a selective iNOS inhibitor [N-(3-(aminomethyl) benzyl)acetamidine] (1400W) or the use of a genetic modified animal (iNOS-knockout mice) markedly reduced iNOS-mediated production of NO and formation of peroxynitrite and consequently significantly decreased myocardial apoptosis and infarct size, showing a crucial link between iNOS-mediated nitrative stress and myocardial injury. In conclusion, chronic beta-AR stimulation up-regulates iNOS expression and increases NO production in the heart, which subsequently markedly enhances formation of reactive nitrogen species/peroxynitrite in the heart, thereby eliciting myocardial apoptosis and potentiating MI/R injury. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/16574780/Chronic_beta_adrenergic_receptor_stimulation_induces_cardiac_apoptosis_and_aggravates_myocardial_ischemia/reperfusion_injury_by_provoking_inducible_nitric_oxide_synthase_mediated_nitrative_stress_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16574780 DB - PRIME DP - Unbound Medicine ER -