Exogenous supplement of glucagon like peptide-1 protects the heart against aortic banding induced myocardial fibrosis and dysfunction through inhibiting mTOR/p70S6K signaling and promoting autophagy.

Abstract

Mammalian target of rapamycin (mTOR) and a ribosomal protein S6 kinase (p70S6K) mediate tissue fibrosis and negatively regulate autophagy. This study aims to investigate whether glucagon-like peptide-1 (GLP-1) analog liraglutide protects the heart against aortic banding-induced cardiac fibrosis and dysfunction through inhibiting mTOR/p70S6K signaling and promoting autophagy activity. Male SD rats were randomly divided into four groups (n = 6/each group): sham operated control; abdominal aortic constriction (AAC); liraglutide treatment during AAC (0.3 mg/kg, injected subcutaneously twice daily); rapamycin treatment during AAC (0.2 mg/kg/day, administered by gastric gavage). Relative to the animals with AAC on week 16, liraglutide treatment significantly reduced heart/body weight ratio, inhibited cardiomyocyte hypertrophy, and augmented plasma GLP-1 level and tissue GLP-1 receptor expression. Phosphorylation of mTOR/p70S6K, populations of myofibroblasts and synthesis of collagen I/III in the myocardium were simultaneously inhibited. Furthermore, autophagy regulating proteins: LC3-II/LC3-I ratio and Beclin-1 were upregulated, and p62 was downregulated by liraglutide. Compared with liraglutide group, treatment with rapamycin, a specific inhibitor of mTOR, compatibly augmented GLP-1 receptor level, inhibited phosphorylation of mTOR/p70S6K and expression of p62 as well as increased level of LC3-II/LC3-I ratio and Beclin-1, suggesting that there is an interaction between GLP-1 and mTOR/p70S6K signaling in the regulation of autophagy. In line with these modifications, treatment with liraglutide and rapamycin significantly reduced perivascular/interstitial fibrosis, and preserved systolic/diastolic function. These results suggest that the inhibitory effects of liraglutide on cardiac fibrosis and dysfunction are potentially mediated by inhibiting mTOR/p70S6K signaling and enhancing autophagy activity.

• Authors: Rong-Hua Zheng, Wei-Wei Zhang, Ye-Nan Ji, Xiao-Jie Bai, Cai-Ping Yan, Jin Wang, Feng Bai, Zhi-Qing Zhao
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 883 Pg. 173318 (Sep 15 2020) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 32621911 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Autophagy-Related Proteins
• Glp1r protein, rat
• Glucagon-Like Peptide-1 Receptor
• Incretins
• Protein Kinase Inhibitors
• Glucagon-Like Peptide 1
• mTOR protein, rat
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases

Topics

• Animals
• Aorta, Abdominal (physiopathology, surgery)
• Autophagy (drug effects)
• Autophagy-Related Proteins (metabolism)
• Disease Models, Animal
• Fibrosis
• Glucagon-Like Peptide 1 (pharmacology)
• Glucagon-Like Peptide-1 Receptor (agonists, metabolism)
• Hypertrophy, Left Ventricular (enzymology, pathology, physiopathology, prevention & control)
• Incretins (pharmacology)
• Ligation
• Male
• Myocytes, Cardiac (drug effects, enzymology, pathology)
• Myofibroblasts (drug effects, enzymology, pathology)
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Rats, Sprague-Dawley
• Ribosomal Protein S6 Kinases, 70-kDa (metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Ventricular Function, Left (drug effects)
• Ventricular Remodeling (drug effects)