Antioxidant Intervention Attenuates Myocardial Neovascularization in Hypercholesterolemia

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

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2109-2115
Number of pages7
JournalCirculation
Volume109
Issue number17
DOIs
StatePublished - May 4 2004

Fingerprint

Hypercholesterolemia
Antioxidants
Hypoxia-Inducible Factor 1
Vascular Endothelial Growth Factor A
Microvessels
Superoxide Dismutase
Atherosclerosis
Oxidative Stress
Vascular Endothelial Growth Factor Receptor-1
Vitamin E
Ascorbic Acid
Myocardial Ischemia
Intercellular Signaling Peptides and Proteins
Up-Regulation
Swine
Cholesterol
Diet
Messenger RNA

Keywords

  • Antioxidant
  • Atherosclerosis
  • Hypercholesterolemia
  • Oxidative stress

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Antioxidant Intervention Attenuates Myocardial Neovascularization in Hypercholesterolemia. / Zhu, Xiang Yang; Rodriguez-Porcel, Martin G; Bentley, Michael D.; Chade, Alejandro R.; Sica, Vincenzo; Napoli, Claudio; Caplice, Noel; Ritman, Erik L.; Lerman, Amir; Lerman, Lilach O.

In: Circulation, Vol. 109, No. 17, 04.05.2004, p. 2109-2115.

Research output: Contribution to journalArticle

Zhu, Xiang Yang ; Rodriguez-Porcel, Martin G ; Bentley, Michael D. ; Chade, Alejandro R. ; Sica, Vincenzo ; Napoli, Claudio ; Caplice, Noel ; Ritman, Erik L. ; Lerman, Amir ; Lerman, Lilach O. / Antioxidant Intervention Attenuates Myocardial Neovascularization in Hypercholesterolemia. In: Circulation. 2004 ; Vol. 109, No. 17. pp. 2109-2115.
@article{90be095d213f41b1af45eb8abe14b904,
title = "Antioxidant Intervention Attenuates Myocardial Neovascularization in Hypercholesterolemia",
abstract = "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.",
keywords = "Antioxidant, Atherosclerosis, Hypercholesterolemia, Oxidative stress",
author = "Zhu, {Xiang Yang} and Rodriguez-Porcel, {Martin G} and Bentley, {Michael D.} and Chade, {Alejandro R.} and Vincenzo Sica and Claudio Napoli and Noel Caplice and Ritman, {Erik L.} and Amir Lerman and Lerman, {Lilach O}",
year = "2004",
month = "5",
day = "4",
doi = "10.1161/01.CIR.0000125742.65841.8B",
language = "English (US)",
volume = "109",
pages = "2109--2115",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "17",

}

TY - JOUR

T1 - Antioxidant Intervention Attenuates Myocardial Neovascularization in Hypercholesterolemia

AU - Zhu, Xiang Yang

AU - Rodriguez-Porcel, Martin G

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

UR - http://www.scopus.com/inward/record.url?scp=2442499548&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=2442499548&partnerID=8YFLogxK

U2 - 10.1161/01.CIR.0000125742.65841.8B

DO - 10.1161/01.CIR.0000125742.65841.8B

M3 - Article

C2 - 15051643

AN - SCOPUS:2442499548

VL - 109

SP - 2109

EP - 2115

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 17

ER -