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Cardioprotection from Myocardial Infarction
1 Department of Medicine, Weill Medical College of Cornell Uninversity, New York, NY, USA
2 Department of Medicine, Weill Medical College of Cornell Uninversity, New York, NY, USA; Department of Cellular and Developmental Biology, Weill Medical College of Cornell University, New York, NY, USA
* To whom correspondence should be addressed. E-mail: jme2002{at}med.cornell.edu.
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
), suggesting that its receptor(s) may be down-regulated 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-, but not 24-month-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 following coronary ligation (TNF-7.9+/-1.9% left ventricular injury [n=4] vs. PBS-16.2+/-7.9% [n=10; P<0.05]). Addition of PDGF-AB did not augment the cardioprotective action of TNF. In myocardial infarctions of older hearts, however, TNF induced significant post-coronary occlusion mortality (TNF-80% vs. PBS-0% [n=10, each; P<0.05]) that was reversed by the co-administration 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.
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