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

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

Research output: Contribution to journalArticle

34 Citations (Scopus)

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)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume285
Issue number2 54-2
StatePublished - Aug 1 2003
Externally publishedYes

Fingerprint

Tumor Necrosis Factor-alpha
Myocardial Infarction
Tumor Necrosis Factor Receptors
Proto-Oncogene Proteins c-sis
Endothelial Cells
Pathology
Peptide Library
Platelet-Derived Growth Factor
Wounds and Injuries
Bacteriophages
Endothelium
Ligation
Blood Vessels
Epitopes
Cardiovascular Diseases
Down-Regulation
Injections
Mortality

Keywords

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

ASJC Scopus subject areas

  • Physiology

Cite this

Age-associated impairment in TNF-α cardioprotection from myocardial infarction. / Cai, Dongqing; Xaymardan, Munira; Holm, Jacquelyne M.; Zheng, Jingang; Kizer, Jorge; Edelberg, Jay M.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 285, No. 2 54-2, 01.08.2003.

Research output: Contribution to journalArticle

Cai, Dongqing ; Xaymardan, Munira ; Holm, Jacquelyne M. ; Zheng, Jingang ; Kizer, Jorge ; Edelberg, Jay M. / Age-associated impairment in TNF-α cardioprotection from myocardial infarction. In: American Journal of Physiology - Heart and Circulatory Physiology. 2003 ; Vol. 285, No. 2 54-2.
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