阿格列扎，一种过氧化物酶体增殖物激活受体-α和-γ双重激动剂，可保护心肌细胞免受高血糖的不利影响。
Aleglitazar, a dual peroxisome proliferator-activated receptor-α and -γ agonist, protects cardiomyocytes against the adverse effects of hyperglycaemia.
作者信息
Chen Yan, Chen Hongmei, Birnbaum Yochai, Nanhwan Manjyot K, Bajaj Mandeep, Ye Yumei, Qian Jinqiao
机构信息
1 Department of Anesthesiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China.
2 Department of Anesthesiology, Kunming Tongren Hospital, Kunming, China.
出版信息
Diab Vasc Dis Res. 2017 Mar;14(2):152-162. doi: 10.1177/1479164116679081. Epub 2017 Jan 23.
PURPOSE
To assess the effects of Aleglitazar on hyperglycaemia-induced apoptosis.
METHODS
We incubated human cardiomyocytes, cardiomyocytes from cardiac-specific peroxisome proliferator-activated receptor-γ knockout or wild-type mice in normoglycaemic or hyperglycaemic conditions (glucose 25 mM). Cells were treated with different concentrations of Aleglitazar for 48 h. We measured viability, apoptosis, caspase-3 activity, cytochrome-C release, total antioxidant capacity and reactive oxygen species formation in the treated cardiomyocytes. Human cardiomyocytes were transfected with short interfering RNA against peroxisome proliferator-activated receptor-α or peroxisome proliferator-activated receptor-γ.
RESULTS
Aleglitazar attenuated hyperglycaemia-induced apoptosis, caspase-3 activity and cytochrome-C release and increased viability in human cardiomyocyte, cardiomyocytes from cardiac-specific peroxisome proliferator-activated receptor-γ knockout and wild-type mice. Hyperglycaemia reduced the antioxidant capacity and Aleglitazar significantly blunted this effect. Hyperglycaemia-induced reactive oxygen species production was attenuated by Aleglitazar in both human cardiomyocyte and wild-type mice cardiomyocytes. Aleglitazar improved cell viability in cells exposed to hyperglycaemia. The protective effect was partially blocked by short interfering RNA against peroxisome proliferator-activated receptor-α alone and short interfering RNA against peroxisome proliferator-activated receptor-γ alone and completely blocked by short interfering RNA to both peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-γ.
CONCLUSION
Aleglitazar protects cardiomyocytes against hyperglycaemia-induced apoptosis by combined activation of both peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-γ in a short-term vitro model.
目的
评估阿格列扎对高血糖诱导的细胞凋亡的影响。
方法
我们将人心肌细胞、心脏特异性过氧化物酶体增殖物激活受体γ基因敲除或野生型小鼠的心肌细胞在正常血糖或高血糖条件下（葡萄糖25 mM）进行培养。细胞用不同浓度的阿格列扎处理48小时。我们测量了处理后的心肌细胞的活力、凋亡、半胱天冬酶-3活性、细胞色素C释放、总抗氧化能力和活性氧生成。用人过氧化物酶体增殖物激活受体α或过氧化物酶体增殖物激活受体γ的短发夹RNA转染人心肌细胞。
结果
阿格列扎减轻了高血糖诱导的人心肌细胞、心脏特异性过氧化物酶体增殖物激活受体γ基因敲除和野生型小鼠心肌细胞的凋亡、半胱天冬酶-3活性和细胞色素C释放，并提高了细胞活力。高血糖降低了抗氧化能力，而阿格列扎显著减弱了这种作用。阿格列扎在人心肌细胞和野生型小鼠心肌细胞中均减轻了高血糖诱导的活性氧生成。阿格列扎改善了暴露于高血糖环境中的细胞的活力。单独针对过氧化物酶体增殖物激活受体α的短发夹RNA和单独针对过氧化物酶体增殖物激活受体γ的短发夹RNA部分阻断了这种保护作用，而针对过氧化物酶体增殖物激活受体α和过氧化物酶体增殖物激活受体γ的短发夹RNA则完全阻断了这种保护作用。
结论
在短期体外模型中，阿格列扎通过联合激活过氧化物酶体增殖物激活受体α和过氧化物酶体增殖物激活受体γ保护心肌细胞免受高血糖诱导的凋亡。
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