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TRANSLATIONAL PHYSIOLOGY

Growth factor-mediated reversal of senescent dysfunction of ischemia-induced cardioprotection

Departments of Medicine, and Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York

Submitted 9 May 2005 ; accepted in final form 22 September 2005

Based on the role of tumor necrosis factor- (TNF-) in ischemic preconditioning (IPC) and the age-associated loss of both TNF--induced platelet-derived growth factor-AB (PDGF-AB)-mediated cardioprotection and IPC-mediated cardioprotection, we hypothesized that targeting of PDGF-AB-based pathways would restore cardioprotection by IPC in the aging heart. To study this, IPC was induced in 4- and 24-mo-old F344 rats. Sections of young hearts isolated 1 day post-IPC revealed increased TNF- compared with controls. In old rats, TNF- was higher at baseline than IPC young rats and was not significantly altered after IPC. Treatment of old rats with PDGF-AB with vascular endothelial growth factor and angiopoietin-2 (a combination termed PVA), but not PDGF-AB alone, at the time of IPC decreased TNF-. In addition, when compared with young hearts, IPC induced greater apoptosis in the old hearts, which was decreased with PVA treatment but was markedly increased with PDGF-AB. To test the significance of these findings, additional rats underwent permanent coronary ligation 1 day post-IPC. IPC was cardioprotective in young rats [14 days postmyocardial infarction (MI), fractional shortening 29 ± 6% vs. control MI 17 ± 4%, P < 0.05; Masson’s trichrome stain MI size: 13 ± 2% vs. control MI 17 ± 4% left ventricular area (LVA); P < 0.05]. In old rats, however, IPC reduced the post-MI 14-day survival (33% vs. controls 67%; P < 0.05). Treatment of IPC-aging rats with PVA, but not PDGF-AB-alone, reversed IPC-induced mortality (PVA-IPC-MI survival, 88%; PDGF-AB-IPC-MI, 14%) and reduced myocardial injury (fractional shortening: PVA-IPC, 31 ± 1% vs. control MI, 21 ± 6%, P < 0.05; MI size: PVA-IPC, 12 ± 2% vs. control MI, 18 ± 3% LVA, P < 0.05) and thus demonstrated that PDGF-AB-based pathways can reverse the senescent impairment in IPC-mediated cardioprotection.

aging; myocardial infarction; preconditioning

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