Abstract
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. In vitro 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.
Highlights
Diabetes as a chronic, metabolic disease has recently attracted widespread attention
Compared with the LFD group, cardiac color Doppler ultrasonography showed that ejection fraction (EF) and fractional shortening (FS) decreased in the High-fat diet (HFD) and ob/ob groups, which indicated a decrease in contractility
Consistent with the effects of BNP mRNA expression, the areas of cardiac myocytes were increased after labeling with α-SMA (Figures 2D,E). These results suggest that the areas and heart failure marker gene BNP were increased after overexpression of PPARγ2 in cardiac myocytes, and this should be evidence that obesity-mediated cardiac hypertrophy and injury may be closely associated with PPARγ2 expression in the myocardium
Summary
Metabolic disease has recently attracted widespread attention. The structure of TZDs was modified to synthesize a novel compound, namely, CMHX008, which has been identified to have a lower PPARγ agonist activity, promote preadipocyte differentiation, and improve insulin sensitivity, with minor influence on weight gain and bone loss compared with rosiglitazone (Ming et al, 2014; Hou et al, 2018). These findings revealed CMHX008 as a new PPARγ partial agonist; it was expected to have a similar efficacy in increasing glucose uptake and potential effects on the risk of cardiovascular events as rosiglitazone. We will further explore the underlying mechanism of cardiac hypertrophy after treatment with CMHX008 and rosiglitazone
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