Age-associated impairment in TNF- cardioprotection from myocardial infarction

Cai, Dongqing, Munira Xaymardan, Jacquelyne M. Holm, Jingang Zheng, Jorge R. Kizer, and Jay M. Edelberg. Age-associated impairment in TNFcardioprotection from myocardial infarction. Am J Physiol Heart Circ Physiol 285: H463–H469, 2003. First published May 8, 2003; 10.1152/ajpheart.00144.2003.—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 TNFreceptor pathways, demonstrating that TNFinduced PDGF-B expression in cardiac microvascular endothelial cells of 4-mo-old, but not 24-mo-old, rats. Moreover, TNFmediated cardioprotective pathways were impaired in the aging heart. In young rat hearts, injection of TNFsignificantly 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, TNFinduced significant postcoronary occlusion mortality (TNF80% 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 TNFreceptor cardiac microvascular pathways may contribute to the increased cardiovasular pathology of the aging heart. Strategies targeted at restoring TNFreceptor-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.