Abstract
SummaryLipotoxicity cardiomyopathy is the result of excessive accumulation and oxidation of toxic lipids in the heart. It is a major threat to patients with diabetes. Glucagon‐like peptide‐1 (GLP‐1) has aroused considerable interest as a novel therapeutic target for diabetes mellitus because it stimulates insulin secretion. Here, we investigated the effects and mechanisms of the GLP‐1 analog exendin‐4 and the dipeptidyl peptidase‐4 inhibitor saxagliptin on cardiac lipid metabolism in diabetic mice (DM). The increased myocardial lipid accumulation, oxidative stress, apoptosis, and cardiac remodeling and dysfunction induced in DM by low streptozotocin doses and high‐fat diets were significantly reversed by exendin‐4 and saxagliptin treatments for 8 weeks. We found that exendin‐4 inhibited abnormal activation of the (PPARα)‐CD36 pathway by stimulating protein kinase A (PKA) but suppressing the Rho‐associated protein kinase (ROCK) pathway in DM hearts, palmitic acid (PA)‐treated rat h9c2 cardiomyocytes (CMs), and isolated adult mouse CMs. Cardioprotection in DM mediated by exendin‐4 was abolished by combination therapy with the PPARα agonist wy‐14643 but mimicked by PPARα gene deficiency. Therefore, the PPARα pathway accounted for the effects of exendin‐4. This conclusion was confirmed in cardiac‐restricted overexpression of PPARα mediated by adeno‐associated virus serotype‐9 containing a cardiac troponin T promoter. Our results provide the first direct evidence that GLP‐1 protects cardiac function by inhibiting the ROCK/PPARα pathway, thereby ameliorating lipotoxicity in diabetic cardiomyopathy.
Highlights
Diabetes mellitus is expected to reach pandemic proportions over the few decades
We investigated the effects of the GLP-1 receptor (GLP-1R) agonist exendin-4 and the dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin on Diabetic cardiomyopathy (DCM) induced by a high-fat diets (HFD) and STZ injections
We demonstrated that the cardioprotective effects of Glucagon-like peptide-1 (GLP-1), including reductions in lipid accumulation and potentiation of antioxidant and anti-apoptosis properties, may be driven by a Peroxisome proliferator-activated receptor alpha (PPARa)-mediated mechanism
Summary
Diabetes mellitus is expected to reach pandemic proportions over the few decades. DCM is defined as structural and functional myocardial impairments in diabetic patients without coronary artery disease or hypertension It is mainly characterized by myocardial hypertrophy and fibrosis, metabolic dysregulation, and defects in myocardial contractile. Cardiacrestricted PPARa overexpression (MHC-PPARa) in mice mimicked the DCM phenotype These animals were relatively more susceptible to serious cardiomyopathy in response to high-fat diets (HFD) or streptozotocin (STZ) stimulation and presented with significant increases in lipids accumulation (Finck et al, 2002, 2003; Yang et al, 2007). Previous studies have shown that GLP-1 and its analogs protected the heart against ischemia-reperfusion injury and diabetes mellitus (Tate, Robinson, Green, McDermott & Grieve, 2016; Wang et al, 2013) They protected isolated CMs from oxidative damage (Chang et al, 2013) and high-glucose stress (Younce, Burmeister & Ayala, 2013). We demonstrated that the cardioprotective effects of GLP-1, including reductions in lipid accumulation and potentiation of antioxidant and anti-apoptosis properties, may be driven by a PPARa-mediated mechanism
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
