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
| Autor: | Jin Wang, Cai-Ping Yan, Feng Bai, Zhi-Qing Zhao, Wei-Wei Zhang, Xiao-Jie Bai, Rong-Hua Zheng, Ye-Nan Ji |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Cardiac fibrosis Receptor expression Autophagy-Related Proteins Pharmacology Incretins Glucagon-Like Peptide-1 Receptor Ventricular Function Left Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Glucagon-Like Peptide 1 medicine Autophagy Animals Myocytes Cardiac Aorta Abdominal Phosphorylation Myofibroblasts Ligation Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Ventricular Remodeling business.industry Liraglutide TOR Serine-Threonine Kinases Ribosomal Protein S6 Kinases 70-kDa medicine.disease Glucagon-like peptide-1 Fibrosis Disease Models Animal 030104 developmental biology Ribosomal protein s6 Myocardial fibrosis Hypertrophy Left Ventricular business 030217 neurology & neurosurgery medicine.drug Signal Transduction |
| Zdroj: | European journal of pharmacology. 883 |
| ISSN: | 1879-0712 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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