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

M Xaymardan, J Zheng, I Duignan, A Chin… - The Journal of …, 2004 - rupress.org
M Xaymardan, J Zheng, I Duignan, A Chin, JM Holm, VLT Ballard, JM Edelberg
The Journal of experimental medicine, 2004rupress.org
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 …
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)–α. In older hearts, PDGF-AB–mediated induction was primarily limited to PDGFR-α. 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.
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