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(Circulation. 2002;105:2206.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Protection of Myocytes From Hypoxia-Reoxygenation Injury by Nitric Oxide Is Mediated by Modulation of Transforming Growth Factor-ß₁

From the Division of Cardiovascular Medicine, Department of Internal Medicine, Physiology, and Biophysics, University of Arkansas for Medical Sciences and Central Arkansas Veterans Health Care System, Little Rock, Ark.

Correspondence to J.L. Mehta, MD, PhD, University of Arkansas for Medical Sciences, 4301 W Markham St, Mail Slot 532, Little Rock, AR 72205-7199. E-mail MehtaJL{at}UAMS.edu

Background— Reoxygenation injury is a result of several complex events, including release of reactive oxygen species, protein kinase C (PKC) activation, and altered expression of transforming growth factor-ß₁ (TGF-ß₁). Nitric oxide (NO) generally protects tissues from reperfusion injury.

Methods and Results— We examined the modulation of TGF-ß₁ expression and activity and PKC activation in cultured rat heart myocytes exposed to a brief period of hypoxia-reoxygenation (H-R) by NO donor 3-morpholino-sydnonimine (SIN-1). H-R resulted in an increased expression of total TGF-ß₁ (mRNA and protein) but a decrease in the release of active TGF-ß₁. Myocyte PKC- protein level was not altered by H-R, but its phosphorylation was augmented. Pretreatment of myocytes with SIN-1 diminished myocyte injury quantified as lactate dehydrogenase release. Simultaneously, release of active TGF-ß ₁ increased and total TGF-ß₁ expression decreased (all P<0.05 versus H-R alone). PKC- phosphorylation increased further in cells treated with SIN-1. The effects of SIN-1 were blocked by the NO scavenger phenyl-tetramethyl-imidazoline-oxyl-oxide as well as by the PKC inhibitor staurosporine. To examine if another NO donor would have a similar effect, cardiomyocytes were treated with nitroglycerin before H-R. With nitroglycerin treatment, similar to SIN-1 treatment, myocyte injury was diminished, TGF-ß ₁ release increased, and total TGF-ß ₁ expression decreased.

Conclusions— These observations suggest modulation of TGF-ß ₁ expression as a novel mechanism of salutary effect of NO donors. PKC- activation may play an important role in the protective effect of NO against H-R injury.

Key Words: hypoxia • nitric oxide • proteins • growth substances

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