Age-associated impairment in TNF-α cardioprotection from myocardial infarction

Dongqing Cai, Munira Xaymardan, Jacquelyne M. Holm, Jingang Zheng, Jorge R. Kizer, Jay M. Edelberg

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)H463-H469
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume285
Issue number2 54-2
DOIs
StatePublished - Aug 1 2003

Keywords

  • Aging
  • Endothelial
  • Functional genomics
  • Heart
  • Phage display

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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