Received for publication March 17, 2005.
Revised September 28, 2005.
Accepted for publication September 29, 2005.

A non-thiazolidinedione PPAR agonist reverses endothelial dysfunction in diabetic (db/db -/-) mice

Abstract

We have previously reported that endothelium-dependent relaxation to acetylcholine is impaired in small mesenteric arteries from spontaneously diabetic (db/db) mice. The objective of the present study was to examine the effects of treatment of the db/db and the insulin resistant ob/ob mice with the PPAR agonist 2-(2-(4-phenoxy-2-propylphenoxy) ethyl) indole-5-acetic acid (COOH). In the db/db model, an 8 week treatment with COOH (30 mg/kg per day) reduced plasma glucose from 48.0 ± 2.5 mM (untreated) to 12.6 ± 1.1 mM. In contrast, plasma glucose was not elevated in untreated ob/ob mice. Relaxation of SMA mediated by acetylcholine was impaired in the untreated db/db diabetic mice (51.7 ± 7.4 % max relaxation, n=6) but not in the ob/ob mice (70.8 ± 8.6% max relaxation, n=3). This impairment was reversed with COOH treatment (86.9 ±0.4 % max relaxation, n=5). Malondialdehyde was elevated in plasma from diabetic db/db mice (13.9± 1.1 vs. 12.0± 0.7 µmoles/ mL), however, when normalized to total cholesterol, no significant differences in the ratio of lipid peroxidation in plasma were identified. Western blot analysis and quantitative PCR for eNOS was performed on the isolated mesenteric vessels and revealed no differences in the relative levels of eNOS expression in diabetic and control animals; in addition, treatment with COOH had no significant effect on eNOS levels in either group. In summary, endothelial dysfunction and hyperglycemia was completely normalized in COOH-treated db/db mice. In contrast, non-hyperglycemic ob/ob mice exhibited normal vasodilatory responses to acetylcholine and consequently COOH treatment had no effect on endothelial function.

Key words: PPARg, diabetes, endothelial function, mouse, nitric oxide, thiazolidinedione

This article has been cited by other articles:

				N. Mzhavia, S. Yu, S. Ikeda, T. T. Chu, I. Goldberg, and H. M. Dansky Neuronatin: A New Inflammation Gene Expressed on the Aortic Endothelium of Diabetic Mice Diabetes, October 1, 2008; 57(10): 2774 - 2783. [Abstract] [Full Text] [PDF]

				A. L. Mundy, E. Haas, I. Bhattacharya, C. C. Widmer, M. Kretz, K. Baumann, and M. Barton Endothelin stimulates vascular hydroxyl radical formation: effect of obesity Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2007; 293(6): R2218 - R2224. [Abstract] [Full Text] [PDF]