Glucagon-like Peptide-1 Ameliorates Cardiac Lipotoxicity In Diabetic Cardiomyopathy Via PPARα Pathway

Background and Objective: Diabetic cardiomyopathy(DCM)is identified as structural and functional impairments of myocardium in diabetic patients without coronary artery disease or high blood pressure,and mainly characterized by myocardial hypertrophy and fibrosis,metabolic dysregulation and defects in myocardial contractile properties.With the aggravation of lipid metabolism disorder,cardiomyocytes and myocardial microvascular lesion,the diabetic hearts finally develop into irreversible heart failure,malignant arrhythmia and cardiogenic shock,which is the leading cause of the death for diabetic patients.Although considerable progression has been achieved,the fact that the molecular etiologies of DCM remain poorly understood and current therapies are not ideal calls the importance and urgency of further research.Native glucagon-like peptide-1(GLP-1)is a gut hormone,produced by L-cells of distal ileum and colon in response to entry of nutrients and destroyed by the circulating enzyme dipeptidyl peptidase-4(DPP-4).In the past decade,GLP-1 analogs and DPP-4 inhibitors have been introduced as a new class of antidiabetic medications for their pleiotropic effects,including increase of glucose-dependent insulin secretion,suppression of glucagon secretion and decrease of appetite and body weight.Previous researches demonstrated that these drugs also had surprising cardioprotective effects that did not depend on their hypoglycemic effects.However,the role of GLP-1 against diabetic cardiomyopathy is not unified and the mechanisms are not yet clear.Therefore,this study was to further clarify the effects of the GLP-1 analogue(Exenatide)and DPP-4 inhibitor(Saxagliptin)on experimental diabetic hearts,and discussed their associations with myocardial lipid metabolism.Methods and Results: 1.Fristly,we established obese/insulin resistance mouse model mimicking human type 2 diabetes with continuous high fat diet and low dose STZ injection.Exendin-4 and saxagliptin treatments for 8 wk significantly attenuated cardiac remodeling,improved cardiac function in diabetic mice and decreased myocardial lipid accumulation,oxidative stress,inflammation and apoptosis,compared with insulin treatment or placebo groups.Therefore,we hypothesize that GLP-1 improves diabetic cardiomyopathy possibly by reducing myocardial lipotoxicity.2.Then,we further studied the effects of GLP-1 on myocardial fat uptake and utilization in vivo and in vitro.We found that Exendin-4 significantly reduced lipid uptake in PA-treated H9C2 cardiomyocytes for their control ability on the PPARa-CD36 pathway,a major signaling for fatty acid transport in hearts.Moreover,we also found Exendin-4 suppressed PPARα transcriptional activity and nuclear translocation though PKA/ROCK-dependent mechanism in diabetic hearts.The Exendin-4-mediated cardioprotection was mimicked by PPARα gene knockout but completely eliminated by treatment of PPARα selective agonist wy-14643 in vitro.Thus,we concluded that Exendin-4 reduced cardiomyocyte lipid accumulation,oxidative stress and apoptosis in PA-treated myocardiocyte via PPARα-mediated mechanism.3.Finally,we used to gene deficiency and r AAV virus treatment to demonstrate the centrol role of PPARα on the GLP-1-mediated protection against cardiac lipotoxicity in vitro.We found that PPARα agonist wy-14643 and cardiac-restricted overexpression of PPARα antagonized Exendin-4’ benefits in diabetic hearts,with increasing myocardial fat accumulation,ROS levels and apoptosis,and decreasing cardiac function.PPARα deficiency mice failed to develop DCM and showed similar cardiac structure and functional characteristics as Exendin-4 treatment group.Conclusion: 1.Both GLP-1 analogue exendin-4 and DDP-4 inhibitor saxagliptin improved diabetes phenotype and its related heart damage,including hyperglycemia,insulin resistance,myocardial remodeling and cardiac dysfunction,which occurred at least partly independently of its established glucose-lowering capacity.2.Exendin-4 suppressed PPARα transcriptional activity and nuclear translocation though PKA/ROCK-dependent mechanism in PA-treated cardiomyocytes,which contributed to the decrease of lipid uptake,ROS production and apoptosis.3.GLP-1 ameliorated myocardial lipid uptake and following lipotoxicity via its PPARα control action.