Effects Of PDE4 Inhibitor On Diabetes Associated Cardiac Dysfunction

Part?The role of?₂AR in cardiac adrenergic reserve impairment in animal heartsObjective:Patients with diabetes display reduced exercise capability and impaired cardiac contractile response to adrenergic stimulation at the early stage.Previous study has shown that insulin impairs cardiac contractility induced by?₁AR in a?₂AR-dependent manner in isolated cardiomyocytes and Langendorff-perfused hearts.Our study aims to understand the impacts of high-fat diet?HFD?on the insulin–adrenergic receptor signal network in hearts.Methods:Wild-type?WT?and?₂AR knockout??₂AR-KO?C57BL/6J mice were randomly assigned to low-fat or high-fat diet for 8 weeks..Echocardiography was used to measure cardiac function and the change of glucose metabolism was detected in vivo.The phosphorylation and total level of?₂AR,signals involved in cardiomyocytes contraction regulated by?₁AR was analyzed by western blot.Cardiac function was detected in?₂AR-KO mice after high-fat diet feeding for 8 weeks.Results:HFD feeding for 8 weeks induced increase of fasting glucose and serum insulin concentration,glucose intolerance and insulin intolerance.There was no obvious change in cardiac function in relative to NC group.Mice fed with HFD didn't exhibite significantly cardiac hypertrophy and fibrosis,while cardiac reserve function was impaired.Compared with NC mice,the totol level of?₂AR was unchanged while the phosphorylation of?₂AR at PKA and GRK sites was increased significantly.Though cAMP level and PLB phosphorylation had no obvious changes after feeding for 8 weeks,cardiomyocytes isolated from HFD mice exhibited impaired cardiac contractile reserve in response to adrenergic stimulation.Inhibition of G_i with PTX can restore the isoproterenol induced PLB phosphorylation in cardiomyocytes from HFD mice.?₂AR-KO mice also exhibited increased fasting glucose and serum insulin concentration,glucose intolerance and insulin intolerance after HFD feeding for 8weeks,while cardiac reserve function was normal.Conclusion:HFD feeding induces?₂AR phosphorylation and promotes?₂AR-G_i coupling through hyperinsulinema,which results in impaired cardiac reserve function before structural remodeling occurs in hearts.Deletion of?₂AR gene ameliorated HFD-induced impairment of cardiac reserve function in hearts.Intervention of the cross-talk of insulin-?₂AR might contribute to the treatment and prevention of diabetic cardiac complications.Part? Effects of PDE4 inhibitor on diabetes associated cardiac dysfunctionObjective:Study in cardiomyocytes has shown that insulin increased the expression of PDE4 in a ?2AR-dependent manner,which results in a reduced contractile shortening response of cardiomyocytes.This part aims to observe the effects of PDE4 inhibitor in HFD induced diabetes associated cardiac dysfunction and its underlying mechanism.Methods:Mice were randomly divided into four groups: NC group,HFD group,ROF+HFD group and HFD+ROF.ROF+HFD group was intragastric administrated with roflumilast?1 mg/kg/day?from the first week of feeding,while HFD + ROF group was intragastric administrated with roflumilast?1 mg/kg/day?from the 16 th week of feeding.Glucose and insulin metabolism and cardiac function were detected every four week in mice.After 20 weeks feeding,the heart was extracted for cardiac histological analysis.Results:Compared with the HFD group,intragastric administrating with roflumilast significantly attenuated glucose intolerance and insulin resistance.The results of echocardiography showed EF and FS of mice administrated with roflumilast were improved.HE staining,Masson staining and Sirius red staining showed cardiac hypertrophy,cardiac fibrosis and collagen synthesis were significantly reduced by roflumilast.Conclusion:PDE inhibitor attenuated cardiac dysfunction,cardiac fibrosis and insulin resistance induced by HFD feeding.PDE4 is a potential target for the treatment of diabetic cardiac insufficiency.