Vasculoprotection by anti-TNF modulation was detailed in September 2000 in my U.S. patent application, which subsequently issued as U.S. patent 6,419,934. My exact words in this patent were " TNF modulation will also have a directly beneficial effect on atherosclerotic vascular disease. Atherosclerosis is accompanied by inflammation in the vessel wall. TNF modulation decreases this inflammation, thereby diminishing the rate of progression of atherosclerosis." (see U.S. patent 6,419,934 B1, column 9, page 6). This intriguing new article by Cisiszar and her colleagues provides experimental evidence in support of these concepts. These concepts, of course, have potential implications for both vascular dementia and Alzheimer's disease.
Title Vasculoprotective Effects of Anti-Tumor Necrosis Factor-{alpha} Treatment in Aging.
Author(s) Csiszar A, Labinskyy N, Smith K, Rivera A, Orosz Z, Ungvari Z
Institution or Zoltan Ungvari, Ph.D., Department of Physiology, New York Medical College, Valhalla, NY 10595. anna_csiszar@nymc.edu.
Source Am J Pathol 2007 Jan; 170(1) :388-698.
Abstract Vascular aging is associated with dysregulation of tumor necrosis factor (TNF)-alpha expression. TNF-alpha is a master regulator of vascular proatherogenic phenotypic changes, and it has been linked to endothelial dysfunction and apoptosis. To test the hypothesis that anti-TNF-alpha treatment exerts vasculoprotective effects in aging, aged (29 months old) F344 rats were treated with etanercept (1 mg/kg/week for 4 weeks), which binds and inactivates TNF-alpha. In aged carotid arteries, relaxations to acetylcholine were decreased, and endothelial O(2)( ) production was increased (as shown by dihydroethidine fluorescence measurements). Etanercept treatment significantly improved responses to acetylcholine and decreased vascular NAD(P)H oxidase activity and expression. In aged carotid and coronary arteries, there were increases in DNA fragmentation rate and caspase 3/7 activity (indicating an increased rate of apoptotic cell death), which were attenuated by etanercept treatment. In aged vessels, there was an up-regulation of inflammatory markers, including inducible nitric-oxide synthase and intercellular adhesion molecule-1, which was decreased by etanercept treatment. In carotid arteries of young animals, recombinant TNF-alpha elicited endothelial dysfunction, oxidative stress, and increased apoptosis and proinflammatory gene expression, mimicking many of the symptoms of vascular aging. Thus, we propose that anti-TNF-alpha treatment exerts anti-aging vasculoprotective effects.
Language eng
Pub Type(s) Journal Article
PubMed ID 17200210
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