Published online before print July 31, 2008, doi: 10.1161/CIRCRESAHA.108.176339
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on March 25, 2008
Revised on July 17, 2008
Accepted on July 23, 2008
Endothelium-Specific Interference With Peroxisome Proliferator Activated Receptor Gamma Causes Cerebral Vascular Dysfunction in Response to a High-Fat Diet
Andreas M. Beyer ;
From the Genetics Graduate Program (A.M.B., C.M.H.), the Department of Internal Medicine (W.J.d.L., M.L.M., H.L.K., F.M.F., C.D.S.), the Department of Pharmacology (F.M.F.), the Department of Molecular Physiology and Biophysics (C.D.S.), and the Center on Functional Genomics of Hypertension (F.M.F.), Cardiovascular Center, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa.
* To whom correspondence should be addressed. E-mail: curt-sigmund{at}uiowa.edu.
The ligand-activated transcription factor PPAR
is expressed in vascular endothelium where it exerts anti-inflammatory and antioxidant effects. However, its role in regulating vascular function remains undefined. We examined endothelial function in transgenic mice expressing dominant-negative mutants of peroxisome proliferator activated receptor gamma (PPAR) under the control of an endothelial-specific promoter to test the hypothesis that endothelial PPAR plays a protective role in the vasculature. Under baseline conditions, responses to the endothelium-dependent agonist acetylcholine were not affected in either aorta or the basilar artery in vitro. In response to feeding a high-fat diet for 12 weeks, acetylcholine produced dilation that was markedly impaired in the basilar artery of mice expressing dominant-negative mutants, but not in mice expressing wild-type PPAR controlled by the same promoter. Unlike basilar artery, 12 weeks of a high-fat diet was not sufficient to cause endothelial dysfunction in the aorta of mice expressing dominant-negative PPAR, although it became evident after 25 weeks. The responses to acetylcholine in basilar artery were restored to normal after treatment with a scavenger of superoxide. Baseline blood pressure was only slightly elevated in the transgenic mice, but the pressor response to angiotensin II was augmented. Thus, interference with PPAR in the endothelium produces endothelial dysfunction in the cerebral circulation through a mechanism involving oxidative stress. Consistent with its role as a fatty acid sensor, these findings provide genetic evidence that endothelial PPAR plays a critical role in protecting a range of blood vessels in response to a high-fat diet.
Key words: endothelium • oxidative stress • transcription • transgenic animals • vascular
This article has been cited by other articles:
 |
|
 |
|
  F.-I Hsieh, W.-C. Lo, H.-J. Lin, Y.-C. Hsieh, L.-M. Lien, C.-H. Bai, H.-P. Tseng, and H.-Y. Chiou Significant Synergistic Effect of Peroxisome Proliferator-Activated Receptor {gamma} C-2821T and Diabetes on the Risk of Ischemic Stroke Diabetes Care, November 1, 2009; 32(11): 2033 - 2035. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Kleinhenz, D. J. Kleinhenz, S. You, J. D. Ritzenthaler, J. M. Hansen, D. R. Archer, R. L. Sutliff, and C. M. Hart Disruption of endothelial peroxisome proliferator-activated receptor-{gamma} reduces vascular nitric oxide production Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1647 - H1654. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Tsukuda, M. Mogi, J. Iwanami, L.-J. Min, A. Sakata, F. Jing, M. Iwai, and M. Horiuchi Cognitive Deficit in Amyloid-{beta}-Injected Mice Was Improved by Pretreatment With a Low Dose of Telmisartan Partly Because of Peroxisome Proliferator-Activated Receptor-{gamma} Activation Hypertension, October 1, 2009; 54(4): 782 - 787. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Chang, L. Villacorta, J. Zhang, M. T. Garcia-Barrio, K. Yang, M. Hamblin, S. E. Whitesall, L. G. D'Alecy, and Y. E. Chen Vascular Smooth Muscle Cell-Selective Peroxisome Proliferator-Activated Receptor-{gamma} Deletion Leads to Hypotension Circulation, April 28, 2009; 119(16): 2161 - 2169. [Abstract] [Full Text] [PDF]
|
|