Published online before print June 26, 2003, doi: 10.1161/01.RES.0000082978.92494.B1
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© 2003 American Heart Association, Inc.
Integrative Physiology |
Aorta of ApoE-Deficient Mice Responds to Atherogenic Stimuli by a Prelesional Increase and Subsequent Decrease in the Expression of Antioxidant Enzymes
From the Division of Biopharmaceutics of the Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands. Present address for P.A.C.’t.H. is the Center for Human and Clinical Genetics, LUMC, Leiden, The Netherlands. Present address for J.T. is Amsterdam Medical Therapeutics, Amsterdam, The Netherlands.
Correspondence to Theo J.C. Van Berkel, LACDR, Division of Biopharmaceutics, PO Box 9502, 2300 RA Leiden, The Netherlands. E-mail t.berkel{at}lacdr.leidenuniv.nl
Oxidative stress has been implicated in the development of atherosclerotic lesions. We evaluated the relationship between extent of atherosclerotic lesion formation and vascular expression of pro- and antioxidant enzymes in apoE-deficient mice. On normal chow, these mice showed elevated serum cholesterol levels (7.5- to 9.5-fold), and age-dependent, spontaneous development of all stages of atherosclerotic lesions, starting at the age of 12 weeks. RNA was extracted from the aortic arch and descending aorta, and mRNA expression of pro- and antioxidant enzymes was measured with real-time PCR. Local infiltration of monocytes/macrophages, reflected by increased vascular expression of CD68 mRNA (>10-fold), indicated that the arch was more susceptible than the descending aorta. The expression of catalase-1 and various isoforms of superoxide dismutase, glutathione peroxidase, and glutathione S-transferase alpha was significantly increased in the aortic arch, but not in the descending aorta, in the period preceding lesion formation (age 6 to 12 weeks). These expression levels were 1.5 to 5 times higher than in age-matched wild-type animals. Remarkably, there was an inverse relationship between extent of lesion formation and the mRNA levels of antioxidant enzymes, most of which started to decline after 12 weeks, as lesions developed. In contrast, inducible nitric oxide synthase expression increased 4-fold in the aortic arch over the course of the disease. Our results suggest that the arterial wall responds to increased serum levels of atherogenic lipoproteins by stimulating expression of antioxidant enzymes. The observed co-ordinate decline in expression of many of these protective systems may greatly accelerate the development of atherosclerosis.
Key Words: oxidative stress • vascular gene expression • real-time PCR • atherosclerosis • redox balance
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