TY - JOUR
T1 - Antioxidant Intervention Attenuates Myocardial Neovascularization in Hypercholesterolemia
AU - Zhu, Xiang Yang
AU - Rodriguez-Porcel, Martin
AU - Bentley, Michael D.
AU - Chade, Alejandro R.
AU - Sica, Vincenzo
AU - Napoli, Claudio
AU - Caplice, Noel
AU - Ritman, Erik L.
AU - Lerman, Amir
AU - Lerman, Lilach O.
PY - 2004/5/4
Y1 - 2004/5/4
N2 - 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)-1α 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-1α, 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/cm 2, 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-1α, 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-1α and VEGF expression and attenuated by antioxidant intervention. This underscores a role of increased oxidative stress in modulating myocardial microvascular architecture in early atherogenesis.
AB - 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)-1α 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-1α, 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/cm 2, 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-1α, 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-1α and VEGF expression and attenuated by antioxidant intervention. This underscores a role of increased oxidative stress in modulating myocardial microvascular architecture in early atherogenesis.
KW - Antioxidant
KW - Atherosclerosis
KW - Hypercholesterolemia
KW - Oxidative stress
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U2 - 10.1161/01.CIR.0000125742.65841.8B
DO - 10.1161/01.CIR.0000125742.65841.8B
M3 - Article
C2 - 15051643
AN - SCOPUS:2442499548
SN - 0009-7322
VL - 109
SP - 2109
EP - 2115
JO - Circulation
JF - Circulation
IS - 17
ER -