This Article Full Text Full Text (PDF) All Versions of this Article: 105/18/2206    most recent 01.CIR.0000015602.94990.3Dv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mehta, J.L. Articles by Li, D.Y. Search for Related Content PubMed PubMed Citation Articles by Mehta, J.L. Articles by Li, D.Y. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Cardiomyopathy Hazardous Substances DB NITRIC OXIDE NITROGLYCERIN Related Collections Biochemistry and metabolism Apoptosis Genomics Growth factors/cytokines Endothelium/vascular type/nitric oxide Mechanism of atherosclerosis/growth factors

(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

This article has been cited by other articles:

				D. J. Hausenloy and D. M. Yellon Cardioprotective growth factors Cardiovasc Res, July 15, 2009; 83(2): 179 - 194. [Abstract] [Full Text] [PDF]

				C.-P. Hu, A. Dandapat, Y. Liu, P. L. Hermonat, and J. L. Mehta Blockade of hypoxia-reoxygenation-mediated collagen type I expression and MMP activity by overexpression of TGF-beta1 delivered by AAV in mouse cardiomyocytes Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1833 - H1838. [Abstract] [Full Text] [PDF]

				Y. Li, G. Takemura, H. Okada, S. Miyata, R. Maruyama, L. Li, M. Higuchi, S. Minatoguchi, T. Fujiwara, and H. Fujiwara Reduction of inflammatory cytokine expression and oxidative damage by erythropoietin in chronic heart failure Cardiovasc Res, September 1, 2006; 71(4): 684 - 694. [Abstract] [Full Text] [PDF]

				J.-S. Huang, L.-Y. Chuang, J.-Y. Guh, C.-J. Chen, Y.-L. Yang, T.-A. Chiang, M.-Y. Hung, and T.-N. Liao Effect of Nitric Oxide-cGMP-Dependent Protein Kinase Activation on Advanced Glycation End-Product-Induced Proliferation in Renal Fibroblasts J. Am. Soc. Nephrol., August 1, 2005; 16(8): 2318 - 2329. [Abstract] [Full Text] [PDF]

				M. Ikeuchi, H. Tsutsui, T. Shiomi, H. Matsusaka, S. Matsushima, J. Wen, T. Kubota, and A. Takeshita Inhibition of TGF-{beta} signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction Cardiovasc Res, December 1, 2004; 64(3): 526 - 535. [Abstract] [Full Text] [PDF]

				T. Waldow, K. Alexiou, W. Witt, F. M. Wagner, V. Gulielmos, K. Matschke, and M. Knaut Attenuation of Reperfusion-Induced Systemic Inflammation by Preconditioning With Nitric Oxide in an In Situ Porcine Model of Normothermic Lung Ischemia Chest, June 1, 2004; 125(6): 2253 - 2259. [Abstract] [Full Text] [PDF]

				F. Eefting, B. Rensing, J. Wigman, W. J. Pannekoek, W. M. Liu, M. J. Cramer, D. J Lips, and P. A Doevendans Role of apoptosis in reperfusion injury Cardiovasc Res, February 15, 2004; 61(3): 414 - 426. [Abstract] [Full Text] [PDF]

				H. Chen, D. Li, T. Saldeen, and J. L. Mehta TGF-beta 1 attenuates myocardial ischemia-reperfusion injury via inhibition of upregulation of MMP-1 Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1612 - H1617. [Abstract] [Full Text] [PDF]