Activation of peroxisome proliferator-activated receptor-{delta} enhances regenerative capacity of human endothelial progenitor cells by stimulating biosynthesis of tetrahydrobiopterin.
Activation of peroxisome proliferator-activated receptor-{delta} enhances regenerative capacity of human endothelial progenitor cells by stimulating biosynthesis of tetrahydrobiopterin.
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DOI：
10.1161/hypertensionaha.111.172189
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发表时间：
2011-08
期刊：
影响因子：
--
通讯作者：
Katusic ZS
中科院分区：
文献类型：
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作者：
He T;Smith LA;Lu T;Joyner MJ;Katusic ZS
内皮祖细胞(EPC)再生能力的机制尚不完全清楚。我们推测四氢生物蝶呤的生物合成是过氧化物酶体增殖物激活受体δ激活对人内皮祖细胞再生功能刺激作用的重要机制。用选择性PPARδ激动剂GW501516处理人内皮祖细胞24 h，可增加GTP环水解酶I(GTPCH I)的表达水平、蛋白水平和酶活性，以及BH4的产生。GW501516的作用是通过抑制PTEN的表达从而增加AKT的磷酸化来实现的。AKT信号还介导了GW501516诱导的内皮型一氧化氮合酶(ENOS)的磷酸化。此外，激活PPARδ可显著促进内皮祖细胞的增殖。这种作用可被GTPCH I抑制剂DAHP或用小干扰RNA基因失活GTPCH I所消除，但不能被L-NAME抑制eNOS。补充NO不能逆转DAHP抑制的BrdU掺入。此外，在颈动脉损伤的小鼠模型中，移植人内皮祖细胞刺激了再内皮化。GW501516可显著增强移植内皮祖细胞对内皮细胞的修复能力。GTPCH I-siRNA可显著抑制GW501516刺激的EPC的体内再生能力。因此，在人内皮祖细胞中，PPARδ的激活通过PTEN-AKT信号通路刺激GTPCH I的表达和活性以及BH4的生物合成。这种作用增强了内皮祖细胞的再生功能。
The mechanisms underlying the regenerative capacity of endothelial progenitor cells (EPCs) are not fully understood. We hypothesized that biosynthesis of tetrahydrobiopterin (BH4) is an important mechanism responsible for the stimulatory effects of peroxisome proliferator-activated receptor delta (PPARδ) activation on regenerative function of human EPCs. Treatment of human EPCs with a selective PPARδ agonist GW501516 for 24 h increased the levels of mRNA, protein, and enzymatic activity of GTP cyclohydrolase I (GTPCH I), as well as the production of BH4. The effects of GW501516 were mediated by suppression of PTEN expression thereby increasing phosphorylation of AKT. The AKT signaling also mediated GW501516-induced phosphorylation of endothelial nitric oxide synthase (eNOS). In addition, activation of PPARδ significantly enhanced proliferation of EPCs. This effect was abolished by the GTPCH I inhibitor, DAHP, or genetic inactivation of GTPCH I with small interfering RNA (siRNA), but not by inhibition of eNOS with L-NAME. Supplementation of NO did not reverse DAHP-inhibited BrdU incorporation. Furthermore, transplantation of human EPCs stimulated re-endothelialization in a mouse model of carotid artery injury. Pretreatment of EPCs with GW501516 significantly enhanced ability of transplanted EPCs to repair denuded endothelium. GTPCH I-siRNA transfection significantly inhibited in vivo regenerative capacity of EPCs stimulated with GW501516. Thus, in human EPCs, activation of PPARδ stimulates expression and activity of GTPCH I and biosynthesis of BH4 via PTEN-AKT signaling pathway. This effect enhances the regenerative function of EPCs.