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Vascular endothelial dysfunction in a rat model of the metabolic syndrome and type 2 diabetes : Role of caveolae and the effect of treatment with

By S.W. Landheer

Abstract

Obesity has become an increasing health concerning problem in the developed world. People who suffer from obesity are at risk of developing the metabolic syndrome. The metabolic syndrome is characterized by a combination of symptoms, including obesity, hypertension, dyslipidemia and type 2 diabetes mellitus. Each of these symptoms itself is a risk factor for the development of cardiovascular disease. The Zucker diabetic fatty (ZDF) rat is a commonly used model to study the metabolic syndrome. These animals develop vascular endothelial dysfunction early in life. This endothelial dysfunction is marked by an impaired production of nitric oxide (NO), a potent vasodilatory substance with vasoprotective properties. Treatment with an angiotensin-1-converting enzyme (ACE) inhibitor improved endothelial function in this rat model. There is an increasing evidence that also peptides, derived from natural food products such as milk and egg, have vasoprotective effects. In in vitro assay studies we identified NWT-03 as a high potential, egg-derived precursor protein of ACE inhibitory peptides. In preliminary in vivo studies, acute ingestion of NWT-03 resulted in inhibition of plasma ACE activity and reduction of blood pressure in spontaneously hypertensive rats. We therefore hypothesized that NWT-03 might favorably affect endothelial dysfunction development in the metabolic syndrome. Therefore, ZDF rats were supplemented with NWT-03 at two different doses for 15 weeks after which endothelium dependent relaxation was assessed in isolated aortic rings in an ex vivo organ bath setup. In a second series of experiments we investigated if short term, 2 week supplementation with nwt-03 could improve vascular endothelial function in the coronary and mesenteric artery of 15 and 25 week old ZDF rats. Therefore, endothelium dependent relaxation was assessed in isolated mesenteric and coronary artery segments in an ex vivo myograph setup. Caveolae, small invaginations in the plasma membrane, are known to influence NO production. Therefore we also assessed the role of caveolar signalling in coronary and mesenteric arteries of ZDF rats. We found that 15 weeks supplementation with the egg hydrolysate nwt-03 improves vascular endothelial function in the oarta of ZDF rats. Short term supplementation with nwt-03 did not improve endothelial dysfunction in mesenteric and coronary arteries. Disruption of endothelial cell caveolae improved endothelial function in the mesenteric artery of 25 week old ZDF rats, indicating that endothelial dysfunction in mesenteric arteries of ZDF rats lead to a change in caveolar signalling. We showed that long term supplementation with food derived peptides can improve endothelial dysfunction in rats with the metabolic syndrome. More research is needed to assess the role of these peptides in the treatment and prevention of endothelial dysfunction in humans.

Year: 2010
OAI identifier: oai:ub.rug.nl:dbi/4df8b04910e27
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