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(Circulation. 2005;112:I-202 – I-207.)
© 2005 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Effects of L-Arginine on Fibroblast Growth Factor 2–Induced Angiogenesis in a Model of Endothelial Dysfunction

Pierre Voisine, MD; Jian Li, MD, PhD; Cesario Bianchi, MD, PhD; Tanveer A. Khan, MD; Marc Ruel, MD, MPH; Shu-Hua Xu, PhD; Jun Feng, MD, PhD; Audrey Rosinberg, MD; Tamer Malik, MD; Yasunari Nakai, MD, PhD; Frank W. Sellke, MD

From the Divisions of Cardiothoracic Surgery (P.V., C.B., T.A.K., S.-H.X., J.F., A.R., T.M., Y.N., F.W.S.) and Cardiology (J.L.), Beth Israel Deaconess Medical Center, Boston, Mass, and the Division of Cardiac Surgery (M.R.), University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

Correspondence to Pierre Voisine, MD, Division of Cardiothoracic Surgery, Laval Hospital, 2725 chemin Ste-Foy, Quebec, Canada. E-mail pierre.voisine{at}chg.ulaval.ca

Background— Nitric oxide availability, which is decreased in advanced coronary artery disease associated with endothelial dysfunction, is an important mediator of fibroblast growth factor-2 (FGF-2)–induced angiogenesis. This could explain the disappointing results of FGF-2 therapy in clinical trials despite promising preclinical studies. We examined the influence of L-arginine supplementation to FGF-2 therapy on myocardial microvascular reactivity and perfusion in a porcine model of endothelial dysfunction.

Methods and Results— Eighteen pigs were fed either a normal (NORM, n=6) or high cholesterol diet, with (HICHOL-ARG, n=6) or without (HICHOL, n=6) L-arginine. All pigs underwent ameroid placement on the circumflex artery and 3 weeks later received surgical FGF-2 treatment. Four weeks after treatment, endothelial-dependent coronary microvascular responses and lateral myocardial perfusion were assessed. Endothelial cell density was determined by immunohistochemistry. FGF-2, fibroblast growth receptor-1, endothelial-derived nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and syndecan-4 levels were determined by immunoblotting. Pigs from the HICHOL group showed endothelial dysfunction in the circumflex territory, which was normalized by L-arginine supplementation. FGF-2 treatment was ineffective in the HICHOL group (circumflex/left anterior descending blood flow ratios: 1.01 (rest) and 1.01 (pace), after and before treatment). Addition of L-arginine improved myocardial perfusion in response to FGF-2 at rest (ratio 1.13, P=0.02 versus HICHOL) but not during pacing (ratio 0.94, P=NS), and was associated with increased protein levels of iNOS and eNOS.

Conclusion— L-arginine supplementation can partially restore the normal response to endothelium-dependent vasorelaxants and myocardial perfusion in response to FGF-2 treatment in a swine model of hypercholesterolemia-induced endothelial dysfunction. These findings suggest a role for L-arginine in combination with FGF-2 therapy for end-stage coronary artery disease.

Key Words: angiogenesis • growth substances • endothelium • nitric oxide

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