This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 100/7/1089    most recent 01.RES.0000264081.78659.45v1 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 Zhang, P. Articles by Chen, Y. Search for Related Content PubMed PubMed Citation Articles by Zhang, P. Articles by Chen, Y. Related Collections Congestive Hypertrophy Oxidant stress

(Circulation Research. 2007;100:1089.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Inducible Nitric Oxide Synthase Deficiency Protects the Heart From Systolic Overload–Induced Ventricular Hypertrophy and Congestive Heart Failure

Ping Zhang^*, Xin Xu^*, Xinli Hu, Elza D. van Deel, Guangshuo Zhu, Yingjie Chen

From the Center of Vascular Biology and Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis.

Correspondence to Yingjie Chen, MD, PhD, University of Minnesota, Mayo Mail Code 508, 420 Delaware St SE, Minneapolis, MN 55455. E-mail chenx106{at}tc.umn.edu

Inducible nitric oxide synthase (iNOS) protein is expressed in cardiac myocytes of patients and experimental animals with congestive heart failure (CHF). Here we show that iNOS expression plays a role in pressure overload–induced myocardial chamber dilation and hypertrophy. In wild-type mice, chronic transverse aortic constriction (TAC) resulted in myocardial iNOS expression, cardiac hypertrophy, ventricular dilation and dysfunction, and fibrosis, whereas iNOS-deficient mice displayed much less hypertrophy, dilation, fibrosis, and dysfunction. Consistent with these findings, TAC resulted in marked increases of myocardial atrial natriuretic peptide 4-hydroxy-2-nonenal (a marker of lipid peroxidation) and nitrotyrosine (a marker for peroxynitrite) in wild-type mice but not in iNOS-deficient mice. In response to TAC, myocardial endothelial NO synthase and iNOS was expressed as both monomer and dimer in wild-type mice, and this was associated with increased reactive oxygen species production, suggesting that iNOS monomer was a source for the increased oxidative stress. Moreover, systolic overload–induced Akt, mammalian target of rapamycin, and ribosomal protein S6 activation was significantly attenuated in iNOS-deficient mice. Furthermore, selective iNOS inhibition with 1400W (6 mg/kg per hour) significantly attenuated TAC induced myocardial hypertrophy and pulmonary congestion. These data implicate iNOS in the maladaptative response to systolic overload and suggest that selective iNOS inhibition or attenuation of iNOS monomer content might be effective for treatment of systolic overload-induced cardiac dysfunction.

Key Words: superoxide anion • peroxynitrite • iNOS monomer • mTOR

This article has been cited by other articles:

				X. Xu, J. Fassett, X. Hu, G. Zhu, Z. Lu, Y. Li, J. Schnermann, R. J. Bache, and Y. Chen Ecto-5'-Nucleotidase Deficiency Exacerbates Pressure-Overload-Induced Left Ventricular Hypertrophy and Dysfunction Hypertension, June 1, 2008; 51(6): 1557 - 1564. [Abstract] [Full Text] [PDF]

				M. J. Kohr, H. Wang, D. G. Wheeler, M. Velayutham, J. L. Zweier, and M. T. Ziolo Targeting of phospholamban by peroxynitrite decreases {beta}-adrenergic stimulation in cardiomyocytes Cardiovasc Res, January 15, 2008; 77(2): 353 - 361. [Abstract] [Full Text] [PDF]

				Z. Lu, X. Xu, X. Hu, G. Zhu, P. Zhang, E. D. van Deel, J. P. French, J. T. Fassett, T. D. Oury, R. J. Bache, et al. Extracellular Superoxide Dismutase Deficiency Exacerbates Pressure Overload Induced Left Ventricular Hypertrophy and Dysfunction Hypertension, January 1, 2008; 51(1): 19 - 25. [Abstract] [Full Text] [PDF]

				M. C. Gongora and D. G. Harrison Sad Heart From No SOD Hypertension, January 1, 2008; 51(1): 28 - 30. [Full Text] [PDF]