title: Inhibition of heat shock protein 90 improves pulmonary arteriole remodeling in pulmonary arterial hypertension.
abstract: While the molecular chaperone heat shock protein 90 (HSP90) is involved in a multitude of physiological and pathological processes, its role relating to pulmonary arterial hypertension (PAH) remains unclear. In the present study, we investigated the effect in which HSP90 improves pulmonary arteriole remodeling, and explored the therapeutic utility of targeting HSP90 as therapeutic drug for PAH. By Elisa and immunohistochemistry, HSP90 was found to be increased in both plasma and membrane walls of pulmonary arterioles from PAH patients. Moreover, plasma HSP90 levels positively correlated with mean pulmonary arterial pressure and C-reactive protein. In a monocrotaline-induced rat model of PH, we found that 17-AAG, a HSP90-inhibitor, alleviated the progress of PH, demonstrated by lower pulmonary arterial pressure and absence of right ventricular hypertrophy. Immunohistochemical staining demonstrated that 17-AAG improved pulmonary arteriole remodeling on the basis of reduced wall thickness and wall area. The inflammatory response attributed to PH could be attenuated by 17-AAG through reduction of NF-κB signaling. Moreover, 17-AAG was found to suppress PDGF-stimulated proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) through induction of cell cycle arrest in the G1 phase. In conclusion, HSP90 inhibitor 17-AAG could improve pulmonary arteriole remodeling via inhibiting the excessive proliferation of PASMCs, and inhibition of HSP90 may represent a therapeutic avenue for the treatment of PAH.
authors.affiliation: Institution of Cardiac Surgery, Department of Cardiovascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Guo-Kun
authors.initials: GK
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Song-Hua
authors.initials: SH
authors.lastname: Li
authors.affiliation: Institution of Cardiac Surgery, Department of Cardiovascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Su-Xuan
authors.initials: SX
authors.lastname: Liu
authors.affiliation: Institution of Cardiac Surgery, Department of Cardiovascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Guan-Xin
authors.initials: GX
authors.lastname: Zhang
authors.affiliation: Institution of Cardiac Surgery, Department of Cardiovascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Institution of Cardiac Surgery, Department of Cardiovascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiology, 98th Military Hospital, Huzhou, Zhejiang, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Cardiology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Xian-Xian
authors.initials: XX
authors.lastname: Zhao
authors.affiliation: Institution of Cardiac Surgery, Department of Cardiovascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Zhi-Yun
authors.initials: ZY
authors.lastname: Xu
mesh_terms: D000328:Adult; D001160:Arterioles / Q000187:drug effects / Q000503:physiopathology; D016227:Benzoquinones / Q000494:pharmacology*; D051358:Cyclin-Dependent Kinase 4 / Q000032:analysis; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4
keywords: Pathology Section; heat shock protein 90; pulmonary arterial hypertension; pulmonary arteriole remodeling; pulmonary artery smooth muscle cells