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TRANSLATIONAL PHYSIOLOGY
cardioprotection from myocardial infarction
Departments of Medicine and Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York 10021
Submitted 18 February 2003 ; accepted in final form 29 April 2003
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-
(TNF-),
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- receptor pathways, demonstrating that TNF- induced PDGF-B
expression in cardiac microvascular endothelial cells of 4-mo-old, but not
24-mo-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 after coronary ligation:
TNF-, 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-. In
myocardial infarctions of older hearts, however, TNF- induced
significant postcoronary occlusion mortality (TNF- 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- 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.
aging; heart; endothelial; phage display; functional genomics
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