Glucagon-like peptide-1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway.

Abstract

Lipotoxicity 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.

• Authors: Lujin Wu, Ke Wang, Wei Wang, Zheng Wen, Peihua Wang, Lei Liu, Dao Wen Wang
• Journal: Aging cell (Aging Cell) Vol. 17 Issue 4 Pg. e12763 (08 2018) ISSN: 1474-9726 [Electronic] England
• PMID: 29659121 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Chemical References

• Dipeptides
• PPAR alpha
• Glucagon-Like Peptide 1
• saxagliptin
• Exenatide
• Adamantane

Topics

• Adamantane (administration & dosage, analogs & derivatives, pharmacology)
• Animals
• Diabetes Mellitus, Experimental (drug therapy, metabolism, pathology)
• Diabetic Cardiomyopathies (drug therapy, metabolism, pathology)
• Dipeptides (administration & dosage, pharmacology)
• Exenatide (administration & dosage, pharmacology)
• Glucagon-Like Peptide 1 (metabolism)
• Lipid Metabolism (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• PPAR alpha (antagonists & inhibitors, genetics, metabolism)