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

Zheng, Jingang, Andrew Chin, Inga Duignan, Kyung-Heon Won, Mun K. Hong, and Jay M. Edelberg. Growth factor-mediated reversal of senescent dysfunction of ischemia-induced cardioprotection. Am J Physiol Heart Circ Physiol 290: H525–H530, 2006. First published September 23, 2005; doi:10.1152/ajpheart.00470.2005.— Based on the role of tumor necrosis factor(TNF) in ischemic preconditioning (IPC) and the age-associated loss of both TNFinduced 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 4and 24-mo-old F344 rats. Sections of young hearts isolated 1 day post-IPC revealed increased TNFcompared with controls. In old rats, TNFwas 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.