Senescent impairment in synergistic cytokine pathways that provide rapid cardioprotection in the rat heart.
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.
Department of Medicine, Greenberg Division of Cardiology, Weill Medical College, Cornell University, New York, NY 10021, USA.
Munira
M
Xaymardan
Jingang
J
Zheng
Inga
I
Duignan
Andrew
A
Chin
Jacquelyne M
JM
Holm
Victoria L T
VL
Ballard
Jay M
JM
Edelberg
D000375:Aging / Q000378:metabolism*; D042702:Angiopoietin-2 / Q000627:therapeutic use*; D000818:Animals; D002316:Cardiotonic Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D003327:Coronary Disease / Q000150:complications; D017931:DNA Primers; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy*; D009206:Myocardium / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000627:therapeutic use*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D042702:Angiopoietin-2; D002316:Cardiotonic Agents; D017931:DNA Primers; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; C095477:platelet-derived growth factor AB; D020796:Receptor, Platelet-Derived Growth Factor alpha; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2