Metformin Prevents Progression of Experimental Pulmonary Hypertension via Inhibition of Autophagy and Activation of Adenosine Monophosphate-Activated Protein Kinase
| Autor: | Honglei Li, Jinquan Zhu, Zengxian Sun, Guangsheng Yang, Yun Liu, Jie Zhang, Yi Xu |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Adenosine monophosphate Physiology Autophagy-Related Proteins AMP-Activated Protein Kinases Pulmonary Artery Vascular Remodeling 030204 cardiovascular system & hematology Pharmacology Muscle Smooth Vascular 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Autophagy medicine Animals Humans Rats Wistar Hypoxia Protein kinase A Cells Cultured Pulmonary Arterial Hypertension Lung Ventricular Remodeling AMPK Hypoxia (medical) medicine.disease Adenosine Pulmonary hypertension Metformin Enzyme Activation Disease Models Animal 030104 developmental biology medicine.anatomical_structure chemistry Disease Progression Ventricular Function Right medicine.symptom Cardiology and Cardiovascular Medicine Signal Transduction medicine.drug |
| Zdroj: | Journal of Vascular Research. 56:117-128 |
| ISSN: | 1423-0135 1018-1172 |
| DOI: | 10.1159/000498894 |
| Popis: | Previous studies have shown that metformin (MET) prevents experimental pulmonary arterial hypertension (PAH) and that activation of autophagy is involved in the development of pulmonary vascular remodeling. However, the mechanism of how MET inhibits autophagy and reverses pulmonary vascular remodeling is still unclear. The objective of the present study was to investigate the role of autophagy in MET-induced hypoxia PAH protection and the underlying mechanisms. To examine the effects of MET on hypoxia, we treated rats with MET (100 mg/kg/day) after 3 weeks of hypoxia. Hemodynamic changes, weight of the right ventricle/left ventricle plus septum (RV/LV+S) ratio, and lung morphological features were examined after 3 weeks. In addition, alpha smooth muscle actin (α-SMA), p62, and PCNA were assessed by immunofluorescence and immunohistochemistry staining. BECN-1, LC3B, p62, and activation of adenosine monophosphate-activated protein kinase (AMPK) were analyzed by Western blotting. Cell proliferation was detected using the Cell Counting Kit-8 (CCK-8) and the 5-ethynyl-2′-deoxyuridine staining kit assay. Hypoxia induced increases in right ventricular systolic pressure and the RV/LV+S ratio, which were attenuated by MET treatment. MET also inhibited hypoxia-induced pulmonary vascular remodeling, collagen deposition, proliferation of pulmonary arterial smooth muscle cells, elevation of BECN-1 and the LC3B-II/-I ratio, and downregulation of p62. Further studies found that this process was mediated by inhibition of autophagy and activation of the AMPK signaling pathway. |
| Databáze: | OpenAIRE |
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