Age-associated impairment in TNF-alpha cardioprotection from myocardial infarction.
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.
Department of Medicine, Weill Medical College of Cornell University, 520 East 70th Street, A352, New York, NY 10021, USA.
Dongqing
D
Cai
Munira
M
Xaymardan
Jacquelyne M
JM
Holm
Jingang
J
Zheng
Jorge R
JR
Kizer
Jay M
JM
Edelberg
D000375:Aging / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000077214:Becaplermin; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019151:Peptide Library; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D015703:Antigens, CD; D019151:Peptide Library; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; C095477:platelet-derived growth factor AB; D000077214:Becaplermin