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Activation of AMPK Prevents Monocrotaline-Induced Extracellular Matrix Remodeling of Pulmonary Artery

Shaojun Li, Dong Han, Yonghong Zhang, Xinming Xie, Rui Ke, Yanting Zhu, Lu Liu, Yang Song, Lan Yang, Manxiang Li

Department of Respiratory Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China (mainland)

Med Sci Monit Basic Res 2016; 22:27-33

DOI: 10.12659/MSMBR.897505

Available online: 2016-03-09

Published: 2016-03-09


BACKGROUND: The current study was performed to investigate the effect of adenosine monophosphate (AMP) – activated protein kinase (AMPK) activation on the extracellular matrix (ECM) remodeling of pulmonary arteries in pulmonary arterial hypertension (PAH) and to address its potential mechanisms.
MATERIAL AND METHODS: PAH was induced by a single intraperitoneal injection of monocrotaline (MCT) into Sprague-Dawley rats. Metformin (MET) was administered to activate AMPK. Immunoblotting was used to determine the phosphorylation and expression of AMPK and expression of tissue inhibitor of metalloproteinase-1 (TIMP-1). Gelatin zymography was performed to determine the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9.
RESULTS: Activation of AMPK by MET significantly reduced the right ventricle systolic pressure and the right ventricular hypertrophy in MCT-induced rat PAH model, and partially inhibited the ECM remodeling of pulmonary arteries. These effects were coupled with the decrease of MMP-2/9 activity and TIMP-1 expression.
CONCLUSIONS: This study suggests that activation of AMPK benefits PAH by inhibiting ECM remodeling of pulmonary arteries. Enhancing AMPK activity might have potential value in clinical treatment of PAH.

Keywords: Disease Models, Animal, Animals, AMP-Activated Protein Kinases - metabolism, Enzyme Activation - drug effects, Extracellular Matrix - pathology, Hypertension, Pulmonary - pathology, Matrix Metalloproteinase 2 - metabolism, Metformin - pharmacology, Monocrotaline - pharmacology, Pulmonary Artery - enzymology, Random Allocation, Rats, Rats, Sprague-Dawley, Tissue Inhibitor of Metalloproteinase-1 - metabolism, Vascular Remodeling - drug effects