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Am J Physiol Heart Circ Physiol 285: H463-H469, 2003. First published May 1, 2003; doi:10.1152/ajpheart.00144.2003
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TRANSLATIONAL PHYSIOLOGY

Age-associated impairment in TNF-{alpha} cardioprotection from myocardial infarction

Dongqing Cai, Munira Xaymardan, Jacquelyne M. Holm, Jingang Zheng, Jorge R. Kizer, and Jay M. Edelberg

Departments of Medicine and Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York 10021

Submitted 18 February 2003 ; accepted in final form 29 April 2003

Age-associated dysfunction in cardiac microvascular endothelial cells with impaired induction of cardioprotective platelet-derived growth factor (PDGF)-dependent pathways suggests that alterations in critical vascular receptor(s) may contribute to the increased severity of cardiovascular pathology in older persons. In vivo murine phage-display peptide library biopanning revealed a senescent decrease in cardiac microvascular binding of phage epitopes homologous to tumor necrosis factor-{alpha} (TNF-{alpha}), suggesting that its receptor(s) may be downregulated in older cardiac endothelial cells. Immunostaining demonstrated that TNF-receptor 1 (TNF-R1) density was significantly lower in the subendocardial endothelium of the aging murine heart. Functional studies confirmed the senescent dysregulation of TNF-{alpha} receptor pathways, demonstrating that TNF-{alpha} induced PDGF-B expression in cardiac microvascular endothelial cells of 4-mo-old, but not 24-mo-old, rats. Moreover, TNF-{alpha} mediated cardioprotective pathways were impaired in the aging heart. In young rat hearts, injection of TNF-{alpha} significantly reduced the extent of myocardial injury after coronary ligation: TNF-{alpha}, 7.9 ± 1.9% left ventricular injury (n = 4) versus PBS, 16.2 ± 7.9% (n = 10; P < 0.05). The addition of PDGF-AB did not augment the cardioprotective action of TNF-{alpha}. In myocardial infarctions of older hearts, however, TNF-{alpha} induced significant postcoronary occlusion mortality (TNF-{alpha} 80% vs. PBS 0%; n = 10 each, P < 0.05) that was reversed by the coadministration of PDGF-AB. Overall, these studies demonstrate that aging-associated alterations in TNF-{alpha} receptor cardiac microvascular pathways may contribute to the increased cardiovasular pathology of the aging heart. Strategies targeted at restoring TNF-{alpha} receptor-mediated expression of PDGF-B may improve cardiac microvascular function and provide novel approaches for treatment and possible prevention of cardiovascular disease in older individuals.

aging; heart; endothelial; phage display; functional genomics



Address for reprint requests and other correspondence: J. M. Edelberg, Weill Medical College of Cornell Univ., 520 East 70th St., A352, New York, NY 10021 (E-mail: jme2002{at}med.cornell.edu).







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