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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online April 22, 2003 as doi:10.1096/fj.02-1049fje. |
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Department of Physiology, New York Medical College, Valhalla, New York, USA
2Correspondence: Department of Physiology, New York Medical College, Valhalla, NY 10595, USA. E-mail: gabor_kaley{at}nymc.edu
SPECIFIC AIMS
Aging alters the phenotype of coronary arteries, which may promote development of ischemic heart disease. The aim of the current study was to characterize in coronary arteries aging-induced alterations in the expression of cytokines, chemokines, and their receptors that may contribute to the phenotypic changes.
PRINCIPAL FINDINGS
1. Proinflammatory shift in cytokine expression profile in aged coronary arteries
We have found that a proinflammatory shift develops in the vascular cytokine expression profile in coronary arteries isolated from Fischer 344 rats with a biological age corresponding to that of 70- to 75-year-old humans. Microarray analysis of gene expression showed that coronary arteries express the mRNA of a wide variety of cytokines, chemokines, and their receptors. Among them, expression of the proinflammatory cytokines TNF-
(3.3x), IL-1ß (3.0x), IL-6 (2.9x), IL-17 (6.1x), and of IL-6R (2.8x), a receptor for IL-6, was significantly increased in aging. Quantitative RT-PCR confirmed these results. Western blot demonstrated that protein expression of TNF- (Fig. 1
), IL-1ß, IL-6, and IL-17 (Fig. 2
) was significantly increased in vessels of aged compared with those of young rats.
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2. Both endothelial and smooth muscle cells produce proinflammatory cytokines in aged coronary arteries
Immunofluorescent double labeling showed that in aged vessels, IL-1ß and IL-6 were predominantly located in the endothelium whereas TNF- (Fig. 1)
and IL-17 (Fig. 2
, confirmed by insitu PCR) was located in smooth muscle. Expression of IL-6R was observed in endothelial, smooth muscle, and adventitial cells (confirmed by insitu PCR). Immunolabeling for the leukocyte markers CD45, CD4, and RMA showed no increased presence of white blood cells in the wall of aged coronary arteries.
CONCLUSIONS AND SIGNIFICANCE
Apart from being a target for circulating cytokines, cells of the coronary arterial wall (endothelial and smooth muscle cells, fibroblasts) produce a wide range of cytokines. Aging seems to be associated with a proinflammatory shift in cytokine expression profile in each vascular cell type within the coronary arteries. Our findings have important clinical implications because seemingly healthy elderly humans exhibit increased circulating levels of proinflammatory cytokines. Other findings show an imbalance in cytokine production in various organ systems in aging. Likely mechanisms that induce vascular expression of proinflammatory cytokines include age-related alterations in the endocrine system, cellular metabolism, and redox regulation, warranting further study.
It seems likely that altered vascular cytokine production modulates the phenotype and thus the function of coronary arteries in an autocrine/paracrine manner. In coronary vessels of aged rats we had previously shown a shift to a prooxidant vascular phenotype including decreased expression of eNOS, increased expression of iNOS, increased activity of NAD(P)H oxidases, increased O2- levels, and peroxynitrite (ONOO-) generation with a consequent decrease in vascular responses mediated by NO. Similar findings have been reported recently in other vascular beds. The action of proinflammatory cytokines is likely to be multifaceted, including down-regulation of eNOS, inhibition of shear stress-induced eNOS phosphorylation, up-regulation of adhesion molecules, and induction of apoptosis. Increased vascular production of TNF- and IL-1ß coupled with an increased sensitivity of vascular cells to cytokine stimulation may also be responsible for the up-regulation of iNOS and NAD(P)H oxidase activity in aged coronary vessels.
Another important finding of our study is that in aged coronary arteries we demonstrated increased expression of the proinflammatory cytokine IL-17, located predominantly in arterial smooth muscle (Fig. 2)
. IL-17 belongs to a recently discovered unique family of cytokines, originally described in T lymphocytes and lately demonstrated in peripheral tissues. The biological actions of IL-17 cytokines are not completely under stood but are likely to include stimulation of the production of other cytokines and chemokines such as IL-6, IL-8, and monocyte chemoattractant proteins in a variety of cell types, including endothelial cells.
In conclusion, we propose that aging induces a proinflammatory shift in the profile of vascular cytokine expression that contributes to the aging-induced phenotypic changes in coronary arteries, promoting the development of ischemic heart disease in the elderly (Fig. 3
).
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-1049fje; to cite this article, use FASEB J. (April 22, 2003) 10.1096/fj.02-1049fje 
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