Cao Xuemei, Mao Min, Diao Junlin, Hou Yi, Su Hong, Gan Yongjun, Li Jibin, Tong Xiaoyong, Wu Chaodong, Zuo Zhong, Xiao Xiaoqiu
Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Front Pharmacol. 2021 Jul 7;12:683156. doi: 10.3389/fphar.2021.683156. eCollection 2021.
The clinical controversy of rosiglitazone as a hypoglycemic agent is potentially associated with heart failure, mainly due to its potent activation of peroxisome proliferator-activated receptor γ (PPARγ). PPARγ partial agonists showed superior pharmacological profiles to rosiglitazone. This study compared differences in cardiac morphology and function of the PPARγ partial agonist CMHX008 with rosiglitazone. High-fat diet (HFD) induced obese mice, ob/ob mice and cardiomyocytes overexpressing PPARγ2 were treated with CMHX008 or rosiglitazone. Heart function, myocardial morphology, and hypertrophy-related gene expression were examined. Clinical information from patients with type 2 diabetes mellitus (T2DM) who had taken rosiglitazone and undergone Doppler echocardiography was collected. HFD and ob/ob mice significantly developed cardiac contractile dysfunction, with upregulated PPARγ2 protein levels in heart tissues. Cardiomyocytes of HFD and ob/ob mice were disorderly arranged, the cell areas expanded, and collagen accumulated. cardiomyocytes overexpressing PPARγ2 displayed obvious structural abnormalities and high mRNA levels of ANP and BNP, critical cardiac hypertrophy-related genes. HFD-fed mice treated with rosiglitazone or CMHX008 had significantly improved cardiac function, but rosiglitazone induced higher expression of ANP and βMHC and hypertrophic cardiomyopathy, while CMHX008 did not. Patients with T2DM taking rosiglitazone exhibited increased thickness of the posterior wall and the ventricular septum, suggesting cardiac hypertrophy. Our findings show that diabetic cardiomyopathy was associated with ectopic overexpression of PPARγ2. The full agonist rosiglitazone prevents cardiac dysfunction at the expense of compensatory hypertrophy, while the partial agonist CMHX008 shared a comparable protective effect without altering the structure of cardiomyocytes.
罗格列酮作为一种降糖药物的临床争议可能与心力衰竭有关，主要是由于其对过氧化物酶体增殖物激活受体γ（PPARγ）的强力激活作用。PPARγ部分激动剂显示出比罗格列酮更优的药理学特性。本研究比较了PPARγ部分激动剂CMHX008与罗格列酮在心脏形态和功能方面的差异。用CMHX008或罗格列酮处理高脂饮食（HFD）诱导的肥胖小鼠、ob/ob小鼠以及过表达PPARγ2的心肌细胞。检测心脏功能、心肌形态以及与肥大相关的基因表达。收集服用罗格列酮并接受多普勒超声心动图检查的2型糖尿病（T2DM）患者的临床信息。HFD和ob/ob小鼠明显出现心脏收缩功能障碍，心脏组织中PPARγ2蛋白水平上调。HFD和ob/ob小鼠的心肌细胞排列紊乱，细胞面积增大，胶原积聚。过表达PPARγ2的心肌细胞表现出明显的结构异常以及心房钠尿肽（ANP）和脑钠肽（BNP）这两个关键的心脏肥大相关基因的高mRNA水平。用罗格列酮或CMHX008处理的HFD喂养小鼠心脏功能显著改善，但罗格列酮诱导ANP和β-肌球蛋白重链（βMHC）更高表达以及肥厚型心肌病，而CMHX008则不会。服用罗格列酮的T2DM患者表现出后壁和室间隔厚度增加,提示心脏肥大。我们的研究结果表明糖尿病性心肌病与PPARγ2的异位过表达有关。完全激动剂罗格列酮以代偿性肥大为代价预防心脏功能障碍，而部分激动剂CMHX008具有类似的保护作用，同时不会改变心肌细胞的结构。
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