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TRANSLATIONAL PHYSIOLOGY

Age-associated impairment in TNF- cardioprotection from myocardial infarction

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- (TNF-), 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- receptor pathways, demonstrating that TNF- induced PDGF-B expression in cardiac microvascular endothelial cells of 4-mo-old, but not 24-mo-old, rats. Moreover, TNF- mediated cardioprotective pathways were impaired in the aging heart. In young rat hearts, injection of TNF- significantly reduced the extent of myocardial injury after coronary ligation: TNF-, 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-. In myocardial infarctions of older hearts, however, TNF- induced significant postcoronary occlusion mortality (TNF- 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- receptor cardiac microvascular pathways may contribute to the increased cardiovasular pathology of the aging heart. Strategies targeted at restoring TNF- 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