The Protective Effect And Mechanism Of A Novel PPAR? Agonist On Diabetic Cardiomyopathy Induced By Diabetes Mellitus

OBJECTIVE: The potential adverse effects of the classic TZDS medications on the heart were associated with clinical controversy.Rosiglitazone as an oral hypoglycemic agent has been accompanied by loss of bone mass,cardiovascular risk,water and sodium retention and so on with long-term use.Its mechanism was not clear yet.And there are many studies dedicating to new PPAR? partial agonists that attenuate side effects.This study was aimed to investigate the relationship between the expression of peroxisome proliferator-activated receptor ?(PPAR?)in cardiac myocardium and cardiac function,and to observe and compare the effects of a novel PPAR? agonist CMHX008 with the full agonist rosiglitazone on insulin sensitization and cardiac function.METHODS: Male C57BL/6J mice were randomly divided into high fat diet(HFD)group,normal diet(LFD)group,and ob / ob mice whose leptin gene knockout.HFD group was randomly divided into CMHX008 group,rosiglitazone group and solvent(Veh group),and LFD-Veh group was used as control group.The cardiac function was measured by color Doppler ultrasonography.H & E staining was used to observe the morphology of myocardium.Q-PCR was used to detect the mRNA expression of gene related to myocardium injury.The cells were treated with CMHX008 and rosiglitazone respectively after transfection with PPAR? 2 plasmids.The morphology of the cells was observed.The expression of related genes was detected by Q-PCR.In addition,the data of patients with type 2 diabetes mellitus who had taken rosiglitazone and a Doppler echocardiography were collected as the experimental group,and the patients with similar age and disease duration were collected as the control,and the differences in cardiac function were compared.Results: The cardiac function of HFD and ob/ob model mice were significantly impaired: the left ventricular diameter shortening fraction,the ejection fraction decreased significantly,the left ventricular diameter increased;the myocardial cell disorder,the gap decreased;PPAR?2 mRNA and Protein is raised.The expression of ANP and BNP mRNA was up-regulated after Mouse Cardiac Myocytes overexpressing PPAR?2.Both CMHX008 and rosiglitazone of same dose had a significant effect on impaired glucose tolerance.Compared with the obese group,the ejection fraction and fraction shortening of rosiglitazone group were increased,but the expression of ANP,BNP and ?-MHC was significantly increased accompanied with the left ventricular posterior wall,ventricular septal thickening which suggesting that myocardial compensatory hypertrophy.CMHX008 treatmentsignificantly improved the cardiac function without obvious performance of compensatory hypertrophy.Meanwhile,clinical data showed that taking Rosiglitazone increased the thickness of the posterior wall and the ventricular septum,which is a mark of cardiac hypertrophy.Conclusion: The overexpression of PPAR?2 in myocardium is a key step in the development of diabetic cardiomyopathy.The novel PPAR? agonist CMHX008 is superior to rosiglitazone in the safety of the heart when improving the insulin resistance.