Antioxidant intervention attenuates myocardial neovascularization in hypercholesterolemia.
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)-1alpha and vascular endothelial growth factor (VEGF).


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-1alpha, 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-1alpha, 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-1alpha and VEGF expression and attenuated by antioxidant intervention. This underscores a role of increased oxidative stress in modulating myocardial microvascular architecture in early atherogenesis.
Zhu
Xiang-Yang
XY
Department of Internal Medicine, Division of Hypertension, Mayo Clinic College of Medicine, Rochester, Minn 55905, USA.
Rodriguez-Porcel
Martin
M
Bentley
Michael D
MD
Chade
Alejandro R
AR
Sica
Vincenzo
V
Napoli
Claudio
C
Caplice
Noel
N
Ritman
Erik L
EL
Lerman
Amir
A
Lerman
Lilach O
LO
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use*; D001161:Arteriosclerosis / Q000209:etiology; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D003326:Coronary Circulation / Q000187:drug effects*; D004036:Diet, Atherogenic; D015237:Dinoprost / Q000097:blood; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000000981:diagnostic imaging; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D021621:Imaging, Three-Dimensional; D017202:Myocardial Ischemia / Q000209:etiology / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D013552:Swine; D014057:Tomography, X-Ray Computed; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D014810:Vitamin E / Q000008:administration & dosage / Q000627:therapeutic use*
D000975:Antioxidants; D002316:Cardiotonic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D014810:Vitamin E; C002744:3-nitrotyrosine; D014443:Tyrosine; D015237:Dinoprost; D013482:Superoxide Dismutase; D001205:Ascorbic Acid