This Article Full Text Full Text (PDF) Data Supplement Data Supplement All Versions of this Article: 118/8/818    most recent CIRCULATIONAHA.107.717702v1 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 Fraccarollo, D. Articles by Bauersachs, J. Search for Related Content PubMed PubMed Citation Articles by Fraccarollo, D. Articles by Bauersachs, J. Related Collections Structure Contractile function Congestive Cardiovascular Pharmacology Animal models of human disease Acute myocardial infarction Chronic ischemic heart disease Endothelium/vascular type/nitric oxide Related Article

(Circulation. 2008;118:818-827.)
© 2008 American Heart Association, Inc.

Heart Failure

Improvement in Left Ventricular Remodeling by the Endothelial Nitric Oxide Synthase Enhancer AVE9488 After Experimental Myocardial Infarction

Daniela Fraccarollo, PhD; Julian D. Widder, MD; Paolo Galuppo, PhD; Thomas Thum, MD, PhD; Dimitrios Tsikas, MD; Michael Hoffmann, MD; Hartmut Ruetten, MD, PhD; Georg Ertl, MD; Johann Bauersachs, MD

From Medizinische Klinik und Poliklinik I, Universitätsklinikum, Julius-Maximilians-Universität Würzburg, Würzburg (D.F., J.D.W., P.G., T.T., M.H., G.E., J.B.); Institut für Klinische Pharmakologie, Medizinische Hochschule, Hannover (D.T.); and Sanofi-Aventis Deutschland GmbH, Frankfurt (H.R.), Germany.

Correspondence to Professor Dr Johann Bauersachs, Medizinische Klinik und Poliklinik I, Universitätsklinikum, Josef-Schneider-Str 2, D-97080 Würzburg, Germany. E-mail j.bauersachs{at}medizin.uni-wuerzburg.de

Received January 26, 2005; accepted June 20, 2008.

Background— Reduced endothelial nitric oxide (NO) bioavailability contributes to the progression of heart failure. In this study, we investigated whether the transcription enhancer of endothelial NO synthase (eNOS) AVE9488 improves cardiac remodeling and heart failure after experimental myocardial infarction (MI).

Methods and Results— Starting 7 days after coronary artery ligation, rats with MI were treated with placebo or AVE9488 (25 ppm) as a dietary supplement for 9 weeks. AVE9488 therapy versus placebo substantially improved left ventricular (LV) function, reduced LV filling pressure, and prevented the rightward shift of the pressure-volume curve. AVE9488 also attenuated the extent of pulmonary edema, reduced LV fibrosis and myocyte cross-sectional area, and prevented the increases in LV gene expression of atrial natriuretic factor, brain natriuretic peptide, and endothelin-1. eNOS protein levels and calcium-dependent NOS activity were decreased in the surviving LV myocardium from placebo MI rats and normalized by AVE9488. The beneficial effects of AVE9488 on LV dysfunction and remodeling after MI were abrogated in eNOS-deficient mice. Aortic eNOS protein expression and endothelium-dependent NO-mediated vasorelaxation were significantly enhanced by AVE9488 treatment after infarction, whereas increased vascular superoxide anion formation was reduced. Moreover, AVE9488 prevented the marked depression of circulating endothelial progenitor cell levels in rats with heart failure after MI.

Conclusions— Long-term treatment with the eNOS enhancer AVE9488 improved LV remodeling and contractile dysfunction after MI. Molecular alterations, circulating endothelial progenitor cell levels, and endothelial vasomotor dysfunction were improved by AVE9488. Pharmacological interventions designed to increase eNOS-derived NO constitute a promising therapeutic approach for the amelioration of postinfarction ventricular remodeling and heart failure.

---

 

CLINICAL PERSPECTIVE

Related Article:

Circulation: Clinical Summaries
Circulation 2008 118: 793-794. [Extract] [Full Text]

This article has been cited by other articles:

				A. Schafer, D. Fraccarollo, J. Widder, M. Eigenthaler, G. Ertl, and J. Bauersachs Inhibition of platelet activation in rats with severe congestive heart failure by a novel endothelial nitric oxide synthase transcription enhancer Eur J Heart Fail, April 1, 2009; 11(4): 336 - 341. [Abstract] [Full Text] [PDF]

				U. Landmesser, K. C. Wollert, and H. Drexler Potential novel pharmacological therapies for myocardial remodelling Cardiovasc Res, February 15, 2009; 81(3): 519 - 527. [Abstract] [Full Text] [PDF]