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.
AuthorsDongqing Cai, Munira Xaymardan, Jacquelyne M Holm, Jingang Zheng, Jorge R Kizer, Jay M Edelberg
JournalAmerican journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 285 Issue 2 Pg. H463-9 (Aug 2003) ISSN: 0363-6135 [Print] United States
PMID12730063 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antigens, CD
  • Peptide Library
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha
  • platelet-derived growth factor AB
  • platelet-derived growth factor BB
  • Aging (metabolism)
  • Animals
  • Antigens, CD (metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Infarction (metabolism, pathology)
  • Myocardium (metabolism, pathology)
  • Peptide Library
  • Platelet-Derived Growth Factor (metabolism, pharmacology)
  • Proto-Oncogene Proteins c-sis
  • Receptors, Tumor Necrosis Factor (metabolism)
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha (metabolism)

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