Department of Cardiology, Second Hospital Affiliated to the Second Military Medical University, Shanghai, China.
Br J Pharmacol. 2009 Dec;158(8):1865-73. doi: 10.1111/j.1476-5381.2009.00450.x.
Advanced glycation end products (AGEs) and endothelial progenitor cells (EPCs) play key roles in pathogenesis of diabetes-related vascular complications. AGEs can induce dysfunction in EPCs. The peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists are widely used in the treatment of type 2 diabetes, and it remains unknown if they could attenuate EPC dysfunction induced by AGEs.
EPCs isolated from healthy adults were cultured with various concentrations of AGEs (0, 50, 100 and 200 mg L(-1)) with or without rosiglitazone (10 nM), antibody for the receptors for AGE-human serum albumin (anti-receptor for advanced glycation end products (RAGE); 50 microg mL(-1)), phosphatidylinositol-3-kinase (PI3K) inhibitor (LY294002, 5 microM), nitric oxide (NO) synthase inhibitor (L-N(G)-nitro-arginine methyl ester (L-NAME), 100 microM) or sodium nitroprusside (SNP, 25 microM). Proliferation, apoptosis, cell adhesion, migration and NO production in EPCs were assessed, and expressions of endothelial NO synthase (eNOS) and Akt were determined.
Number, proliferation/migration capacities, eNOS and Akt phosphorylation as well as NO synthesized by EPCs were increased by rosiglitazone and reduced by AGEs. AGEs promoted while rosiglitazone reduced EPC apoptosis. The AGE-induced effects were significantly ameliorated by pre-incubation with rosiglitazone, RAGE antibody and SNP. The beneficial effects of rosiglitazone could be blocked by pretreatment with L-NAME and LY294002.
The PPARgamma agonist rosiglitazone increased EPC function and attenuated EPC dysfunction induced by AGEs via upregulating the Akt-eNOS signal pathways of EPCs.
晚期糖基化终产物（AGEs）和内皮祖细胞（EPCs）在糖尿病相关血管并发症的发病机制中起着关键作用。AGEs 可诱导 EPC 功能障碍。过氧化物酶体增殖物激活受体-γ（PPARγ）激动剂广泛用于治疗 2 型糖尿病，但尚不清楚它们是否可以减轻 AGEs 诱导的 EPC 功能障碍。
从健康成年人中分离的 EPC 用不同浓度的 AGEs（0、50、100 和 200mg/L）与或不与罗格列酮（10nM）、AGE-人血清白蛋白受体的抗体（抗晚期糖基化终产物受体（RAGE）；50μg/mL）、磷脂酰肌醇-3-激酶（PI3K）抑制剂（LY294002，5μM）、一氧化氮（NO）合酶抑制剂（L-N（G）-硝基-精氨酸甲酯（L-NAME），100μM）或硝普钠（SNP，25μM）孵育。评估 EPC 的增殖、凋亡、细胞黏附、迁移和 NO 生成，并测定内皮型一氧化氮合酶（eNOS）和 Akt 的表达。
罗格列酮增加了 EPC 的数量、增殖/迁移能力、eNOS 和 Akt 的磷酸化以及 EPC 合成的 NO，而 AGEs 则降低了这些指标。AGEs 促进了 EPC 凋亡，而罗格列酮则减少了 EPC 凋亡。用罗格列酮、RAGE 抗体和 SNP 预先孵育可显著改善 AGE 诱导的作用。用 L-NAME 和 LY294002 预处理可阻断罗格列酮的有益作用。
PPARγ 激动剂罗格列酮通过上调 EPC 的 Akt-eNOS 信号通路，增加了 EPC 的功能，并减轻了 AGEs 诱导的 EPC 功能障碍。
