Cui Zhai1, Nana Zhang2, Jian Wang3, Meng Cao1, Jing Luan1, Huan Liu1, Qianqian Zhang3, Yanting Zhu4, Yuxin Xue1, Shaojun Li5. 1. Shaanxi Key Laboratory of Brain Disorders, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, 710021, Shaanxi, People's Republic of China. 2. Center for Regenerative and Reconstructive Medicine, Med-X Institute of the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China. 3. Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, No.277, West Yanta Road, Xi'an, 710061, Shaanxi, People's Republic of China. 4. Center of Nephropathy and Hemodialysis, Shaanxi Provincial People's Hospital, Xi'an, 710068, Shaanxi, People's Republic of China. 5. Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, No.277, West Yanta Road, Xi'an, 710061, Shaanxi, People's Republic of China. lishaojun0110@126.com.
Abstract
PURPOSE: It has been shown that activation of autophagy promotes the development of pulmonary arterial hypertension (PAH). Meanwhile, forkhead box M1 (FOXM1) has been found to induce autophagy in several types of cancer. However, it is still unclear whether FOXM1 mediates autophagy activation in PAH, and detailed mechanisms responsible for these processes are indefinite. METHOD: PAH was induced by a single intraperitoneal injection of monocrotaline (MCT) to rats. The right ventricle systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), percentage of medial wall thickness (%MT), α-smooth muscle actin (α-SMA) staining, and Ki67 staining were performed to evaluate the development of PAH. The protein levels of FOXM1, phospho-focal adhesion kinase (p-FAK), FAK, and LC3B were determined by immunoblotting or immunohistochemistry. RESULTS: FOXM1 protein level and FAK activity were significantly increased in MCT-induced PAH rats, this was accompanied with the activation of autophagy. Pharmacological inhibition of FOXM1 or FAK suppressed MCT-induced autophagy activation, decreased RVSP, RVHI and %MT in MCT-induced PAH rats, and inhibited the proliferation of pulmonary arterial smooth muscle cells and pulmonary vessel muscularization in MCT-induced PAH rats. CONCLUSION: FOXM1 promotes the development of PAH by inducing FAK phosphorylation and subsequent activation of autophagy in MCT-treated rats.
PURPOSE: It has been shown that activation of autophagy promotes the development of pulmonary arterial hypertension (PAH). Meanwhile, forkhead box M1 (FOXM1) has been found to induce autophagy in several types of cancer. However, it is still unclear whether FOXM1 mediates autophagy activation in PAH, and detailed mechanisms responsible for these processes are indefinite. METHOD: PAH was induced by a single intraperitoneal injection of monocrotaline (MCT) to rats. The right ventricle systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), percentage of medial wall thickness (%MT), α-smooth muscle actin (α-SMA) staining, and Ki67 staining were performed to evaluate the development of PAH. The protein levels of FOXM1, phospho-focal adhesion kinase (p-FAK), FAK, and LC3B were determined by immunoblotting or immunohistochemistry. RESULTS: FOXM1 protein level and FAK activity were significantly increased in MCT-induced PAH rats, this was accompanied with the activation of autophagy. Pharmacological inhibition of FOXM1 or FAK suppressed MCT-induced autophagy activation, decreased RVSP, RVHI and %MT in MCT-induced PAH rats, and inhibited the proliferation of pulmonary arterial smooth muscle cells and pulmonary vessel muscularization in MCT-induced PAH rats. CONCLUSION: FOXM1 promotes the development of PAH by inducing FAK phosphorylation and subsequent activation of autophagy in MCT-treated rats.
Authors: Lu Long; Xudong Yang; Mark Southwood; Junyu Lu; Stefan J Marciniak; Benjamin J Dunmore; Nicholas W Morrell Journal: Circ Res Date: 2013-02-27 Impact factor: 17.367