Published Online
on March 29, 2004

A more recent version of this article appeared on May 4, 2004

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Submitted on March 20, 2003
Revised on January 9, 2004
Accepted on January 14, 2004

Antioxidant Intervention Attenuates Myocardial Neovascularization in Hypercholesterolemia

Xiang-Yang Zhu MD, PhD, Martin Rodriguez-Porcel MD, Michael D. Bentley PhD, Alejandro R. Chade MD, Vincenzo Sica MD, Claudio Napoli MD, PhD, Noel Caplice MD, PhD, Erik L. Ritman MD, PhD, Amir Lerman MD, and Lilach O. Lerman MD, PhD^*

From the Department of Internal Medicine, Divisions of Hypertension (X.-Y.Z., A.R.C., L.O.L.) and Cardiovascular Diseases (M.R.-P., N.C., A.L., L.O.L.), and Department of Physiology and Biomedical Engineering (E.R.L.), Mayo Clinic, Rochester, Minn; the Department of Biological Sciences, Minnesota State University, Mankato (M.D.B.); the Departments of Clinical Pathology and Medicine, University of Naples, Italy (V.S., C.N.); and the Department of Cardiology, Xin-hua Hospital, Shanghai, China (X.Z.).

^* To whom correspondence should be addressed. E-mail: lerman.lilach{at}mayo.edu.

Background--Hypercholesterolemia (HC) and atherosclerosis can elicit oxidative stress, coronary endothelial dysfunction, and myocardial ischemia, which may induce growth-factor expression and lead to myocardial neovascularization. We tested the hypothesis that chronic antioxidant intervention in HC would attenuate neovascularization and preserve the expression of hypoxia-inducible factor (HIF)-1 and vascular endothelial growth factor (VEGF).

Methods and Results--Three groups of pigs (n=6 each) were studied after 12 weeks of normal or 2% HC diet or HC+antioxidant supplementation (100 IU/kg vitamin E and 1 g vitamin C daily). Myocardial samples were scanned ex vivo with a novel 3D micro-CT scanner, and the spatial density and tortuosity of myocardial microvessels were determined in situ. VEGF mRNA, protein levels of VEGF and VEGF receptor-1, HIF-1, nitrotyrosine, and superoxide dismutase (SOD) were determined in myocardial tissue. The HC and HC+antioxidant groups had similar increases in serum cholesterol levels. HC animals showed an increase in subendocardial spatial density of microvessels compared with normal (160.5±11.8 versus 95.3±8.2 vessels/cm², P<0.05), which was normalized in HC+antioxidant (92.5±20.5 vessels/cm², P<0.05 versus HC), as was arteriolar tortuosity. In addition, HC induced upregulation of VEGF, HIF-1, and nitrotyrosine expression and decreased SOD expression and activity, all of which were preserved by antioxidant intervention.

Conclusions--Changes in myocardial microvascular architecture invoked by HC are accompanied by increases in HIF-1 and VEGF expression and attenuated by antioxidant intervention. This underscores a role of increased oxidative stress in modulating myocardial microvascular architecture in early atherogenesis.

Key words: antioxidant • atherosclerosis • hypercholesterolemia • oxidative stress

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