Aleglitazar, a Balanced Dual PPARα and -γ Agonist, Protects the Heart Against Ischemia-Reperfusion Injury
Aleglitazar, a Balanced Dual PPARα and -γ Agonist, Protects the Heart Against Ischemia-Reperfusion Injury
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Aleglitazar 是一种平衡的双 PPARα 和 γ 激动剂，可保护心脏免受缺血再灌注损伤。
DOI：
10.1007/s10557-016-6650-9
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发表时间：
2016-04-01
影响因子：
3.4
通讯作者：
Ye, Yumei
中科院分区：
文献类型：
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作者：
Qian, Jinqiao;Chen, Hongmei;Ye, Yumei
目的 评估 PPARa/gamma 双重激动剂阿格列扎 (Ale) 对心肌缺血再灌注损伤的保护作用是否具有累加作用。 方法 对人心肌细胞 (HCM)、心脏特异性 PPAR gamma 敲除 (MCM-PPAR gamma(CKO)) 或野生型 (MCM-WT) 小鼠的心肌细胞进行研究 与不同浓度的 Ale 一起孵育，并进行模拟缺血再灌注 (SIR) 或常氧条件 (NSIR)。测定细胞活力、细胞凋亡和 caspase-3 活性。 HCM 用针对 PPAR α (siPPAR α) 或 PPAR γ (siPPAR γ) 的 siRNA 转染，然后与 Ale 一起孵育。测量 PPAR α/γ DNA 结合能力。评估了细胞活力、细胞凋亡以及 P-AKT 和 P-eNOS 的水平。在用媒介物、Ale 或格列美脲预处理 3 天后，对 WT 和 db/db 糖尿病小鼠进行 30 分钟冠状动脉闭塞和 24 小时再灌注后的梗塞面积评估。结果 Ale（浓度为 150-600 nM）增加了暴露于 SIR 的 HCM、MCM-WT 和 MCM-PPAR(CKO) 中的细胞活力并减少了细胞凋亡。在 HCM 中，单独的 siPPAR α 或单独的 siPPAR γ 可以部分阻断保护作用，而 siPPAR α + siPPAR γ 可以完全阻断保护作用。啤酒可增加 HCM 中的 P-Akt/P-eNOS。当单独使用 PPAR α、单独使用 PPAR γ 时，特别是当两者都被敲低时，P-Akt 或 P-eNOS 水平会降低。腹膜 GTT 显示 db/db 小鼠的葡萄糖耐量和胰岛素敏感性受损，通过 Ale 或格列美脲治疗使这些症状恢复正常。在缺血再灌注后，麦芽糖（但格列美脲）限制了 WT 和糖尿病小鼠的梗塞面积。 结论 在体外，麦芽糖醇可防止缺氧-复氧引起的心肌细胞凋亡，并可减少体内梗塞面积。
Purpose To evaluate whether aleglitazar (Ale), a dual PPARa/gamma agonist, has additive effects on myocardial protection against ischemia-reperfusion injury.Methods Human cardiomyocytes (HCMs), cardiomyocytes from cardiac-specific PPAR gamma knockout (MCM-PPAR gamma(CKO)) or wild type (MCM-WT) mice were incubated with different concentrations of Ale, and subjected to simulated ischemia-reperfusion (SIR) or normoxic conditions (NSIR). Cell viability, apoptosis and caspase-3 activity were determined. HCMs were transfected with siRNA against PPAR alpha (siPPAR alpha) or PPAR gamma (siPPAR gamma) followed by incubation with Ale. PPAR alpha/gamma DNA binding capacity was measured. Cell viability, apoptosis and levels of P-AKT and P-eNOS were assessed. Infarct size following 30 min coronary artery occlusion and 24 h reperfusion were assessed in WT and db/db diabetic mice following 3-day pretreatment with vehicle, Ale or glimeperide.Results Ale (at concentrations of 150-600 nM) increased cell viability and reduced apoptosis in HCMs, MCM-WT and MCM-PPAR(CKO) exposed to SIR. In HCM, the protective effect was partially blocked by siPPAR alpha alone or siPPAR gamma alone, and completely blocked by siPPAR alpha+siPPAR gamma. Ale increased P-Akt/P-eNOS in HCMs. P-Akt or P-eNOS levels were decreased when PPAR alpha alone, PPAR gamma alone and especially when both were knocked down. Peritoneal GTTs revealed that db/db mice had developed impaired glucose tolerance and insulin sensitivity, which were normalized by Ale or glimepiride treatment. Ale, but not glimepiride, limited infarct size in both WT and diabetic mice after ischemia-reperfusion.Conclusions Ale protects against myocardial apoptosis caused by hypoxia-reoxygenation in vitro and reduces infarct size in vivo.