Ann Thorac Surg 2006;81:642
© 2006 The Society of Thoracic Surgeons
Original article: Cardiovascular
Invited commentary
Yoshifumi Naka, MD, PhD,
Dmitri Belov, MD
Division of Surgery, Columbia University, Milstein Building, 177 Fort Washington Ave, New York, NY 310032
(Email: yn33{at}columbia.edu; db711{at}columbia.edu).
This article by Boodhwani and colleagues [1] evaluates the possible mechanisms responsible for impairment of ischemia-induced angiogenesis by hypercholesterolemia. The single most important observation made in this report is that hypercholesterolemia directly impairs the balance of stimulatory and inhibitory factors of angiogenesis. The production of endostatin was significantly upregulated in the group with a high cholesterol level. Endostatin is a 20 kilodalton collagen XVIII-derived endogenous inhibitor, which suppresses the proliferation and migration of endothelial cells, and also affects their survival by induction of apoptotic pathways. Compared to control animals, ones that received high-lipid diet showed no difference in angiostatin production. Angiostatin-dependent impairment of collateral vessel formation might be more important in conditions of chronic hyperglycemia [2] rather then hypercholesterolemia. The findings made by the authors [1] raise an important question of whether endostatin production by vascular smooth muscle cells represents a compensatory response to a pro-atherogenic environment or just an epiphenomenon. In murine studies, endostatin attenuates atherosclerotic plaque formation by disruption of neovascularization [3] and is likely to be responsible for a smaller frequency of diabetic retinopathy and atherosclerosis in individuals with Down syndrome [4]. A complex interaction between pro-atherogenic and anti-angiogenic factors may exist.
Furthermore, Boodhwani and colleagues [1] did not observe any difference in endothelial nitric oxide synthase (eNOS) expression between the two groups. The authors speculate that the increased nitric oxide nitric oxide (NO) degradation by rapid oxidation impairs NO bioavailability, which fits into the widely accepted paradigm of cholesterol-induced oxidative endothelial stress. However, other mechanisms such as competitive inhibition of eNOS by asymmetric dimethylarginine may represent a potential significance.
In summary, Boodhwani and colleagues [1] made a novel important association between diet-induced hypercholesterolemia, endostatin production, and the development of collateral circulation.
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References
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- Boodhwani M, Nakai Y, Mienoi S, et al. Hypercholesterolemia impairs the myocardial angiogenic response in a swine model of chronic ischemiarole of endostatin and oxidative stress. Ann Thorac Surg 2006;81:634-642.[Abstract/Free Full Text]
- Weihrauch D, Lohr NL, Mraovic B, et al. Chronic hyperglycemia attenuates coronary collateral development and impairs proliferative properties of myocardial interstitial fluid by production of angiostatin Circulation 2004;109:2343-2348.[Abstract/Free Full Text]
- Moulton KS, Heller E, Konerding MA, et al. Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E–deficient mice Circulation 1999;99:1726-1732.[Abstract/Free Full Text]
- Zorick TS, Mustacchi Z, Bando SY, et al. High serum endostatin levels in Down syndromeimplications for improved treatment and prevention of solid tumours. Eur J Hum Genet 2001;9:811-814.[Medline]
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