Senescent impairment in synergistic cytokine pathways that provide rapid cardioprotection in the rat heart

• Published in: The Journal of experimental medicine Vol. 199; no. 6; pp. 797 - 804
• Main Authors: Xaymardan, Munira, Zheng, Jingang, Duignan, Inga, Chin, Andrew, Holm, Jacquelyne M, Ballard, Victoria L T, Edelberg, Jay M
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 15.03.2004
• Subjects: Aging - metabolism; Angiopoietin-2 - therapeutic use; Animals; Cardiotonic Agents - therapeutic use; Cells, Cultured; Coronary Disease - complications; DNA Primers; Drug Synergism; Gene Expression Regulation - drug effects; Immunohistochemistry; In Situ Nick-End Labeling; Mice; Mice, Inbred C57BL; Myocardial Infarction - complications; Myocardial Infarction - drug therapy; Myocardium - metabolism; Platelet-Derived Growth Factor - therapeutic use; Rats; Rats, Inbred F344; Receptor, Platelet-Derived Growth Factor alpha - metabolism; Receptor, TIE-2 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Vascular Endothelial Growth Factor A - therapeutic use; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20031639

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)-alpha. In older hearts, PDGF-AB-mediated induction was primarily limited to PDGFR-alpha. 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.