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Department of Medicine, Greenberg Division of Cardiology and Department of Cell and Developmental Biology, Weill Medical College, Cornell University, New York, NY 10021

Address correspondence to Jay M. Edelberg, Weill Medical College, Cornell University, Dept. of Medicine, Greenberg Division of Cardiology, 525 E. 68th St., A352, New York, NY 10021. Phone: (212) 746-1361; Fax: (212) 746-1181; email: jme2002{at}med.cornell.edu

Pretreatment of rodent hearts with platelet-derived growth factor (PDGF)–AB decreases myocardial injury after coronary occlusion. However, PDGF-AB cardioprotection is diminished in older animals, suggesting that downstream elements mediating and/or synergizing the actions of PDGF-AB may be limited in aging cardiac vasculature. In vitro PDGF-AB induced vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-2 expression in 4-mo-old rat cardiac endothelial cells, but not in 24-mo-old heart cells. In vivo injection of young hearts with PDGF-AB increased densities of microvessels staining for VEGF and its receptor, Flk-1, and Ang-2 and its receptor, Tie-2, as well as PDGF receptor (PDGFR)–. In older hearts, PDGF-AB–mediated induction was primarily limited to PDGFR-. Studies in a murine cardiac transplantation model demonstrated that synergist interactions of PDGF-AB plus VEGF plus Ang-2 (PVA) provided an immediate restoration of senescent cardiac vascular function. Moreover, PVA injection in young rat hearts, but not PDGF-AB alone or other cytokine combinations, at the time of coronary occlusion suppressed acute myocardial cell death by >50%. However, PVA also reduced the extent of myocardial infarction with an age-associated cardioprotective benefit (4-mo-old with 45% reduction vs. 24-mo-old with 24%; P < 0.05). These studies showed that synergistic cytokine pathways augmenting the actions of PDGF-AB are limited in older hearts, suggesting that strategies based on these interactions may provide age-dependent clinical cardiovascular benefit.

Key Words: platelet-derived growth factor • vascular endothelial growth factor • angiopoietin • myocardial infarction • apoptosis

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