title: Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice.
abstract: Endothelial AMP-activated protein kinase (AMPK) plays an important role for vascular homeostasis, and its role is impaired by vascular inflammation. However, the role of endothelial AMPK in the pathogenesis of pulmonary arterial hypertension (PAH) remains to be elucidated.
  
  
  
  To determine the role of endothelial AMPK in the development of PAH.
  
  
  
  Immunostaining showed that endothelial AMPK is downregulated in the pulmonary arteries of patients with PAH and hypoxia mouse model of pulmonary hypertension (PH). To elucidate the role of endothelial AMPK in PH, we used endothelial-specific AMPK-knockout mice (eAMPK(-/-)), which were exposed to hypoxia. Under normoxic condition, eAMPK(-/-) mice showed the normal morphology of pulmonary arteries compared with littermate controls (eAMPK(flox/flox)). In contrast, development of hypoxia-induced PH was accelerated in eAMPK(-/-) mice compared with controls. Furthermore, the exacerbation of PH in eAMPK(-/-) mice was accompanied by reduced endothelial function, upregulation of growth factors, and increased proliferation of pulmonary artery smooth muscle cells. Importantly, conditioned medium from endothelial cells promoted pulmonary artery smooth muscle cell proliferation, which was further enhanced by the treatment with AMPK inhibitor. Serum levels of inflammatory cytokines, including tumor necrosis factor-α and interferon-γ were significantly increased in patients with PAH compared with healthy controls. Consistently, endothelial AMPK and cell proliferation were significantly reduced by the treatment with serum from patients with PAH compared with controls. Importantly, long-term treatment with metformin, an AMPK activator, significantly attenuated hypoxia-induced PH in mice.
  
  
  
  These results indicate that endothelial AMPK is a novel therapeutic target for the treatment of PAH.
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (J.O., K.S., N.K., T.S., R.K., M.N., T.O., K.K., K.N., K.S., S.S., S.T., T.A., K.S., S.M., H.S.); and Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (Y.H., Y.O.).
authors.forename: Junichi
authors.initials: J
authors.lastname: Omura
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (J.O., K.S., N.K., T.S., R.K., M.N., T.O., K.K., K.N., K.S., S.S., S.T., T.A., K.S., S.M., H.S.); and Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (Y.H., Y.O.).
authors.forename: Kimio
authors.initials: K
authors.lastname: Satoh
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (J.O., K.S., N.K., T.S., R.K., M.N., T.O., K.K., K.N., K.S., S.S., S.T., T.A., K.S., S.M., H.S.); and Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (Y.H., Y.O.).
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kikuchi
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (J.O., K.S., N.K., T.S., R.K., M.N., T.O., K.K., K.N., K.S., S.S., S.T., T.A., K.S., S.M., H.S.); and Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (Y.H., Y.O.).
authors.forename: Taijyu
authors.initials: T
authors.lastname: Satoh
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (J.O., K.S., N.K., T.S., R.K., M.N., T.O., K.K., K.N., K.S., S.S., S.T., T.A., K.S., S.M., H.S.); and Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (Y.H., Y.O.).
authors.forename: Ryo
authors.initials: R
authors.lastname: Kurosawa
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (J.O., K.S., N.K., T.S., R.K., M.N., T.O., K.K., K.N., K.S., S.S., S.T., T.A., K.S., S.M., H.S.); and Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (Y.H., Y.O.).
authors.forename: Masamichi
authors.initials: M
authors.lastname: Nogi
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (J.O., K.S., N.K., T.S., R.K., M.N., T.O., K.K., K.N., K.S., S.S., S.T., T.A., K.S., S.M., H.S.); and Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (Y.H., Y.O.).
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Otsuki
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (J.O., K.S., N.K., T.S., R.K., M.N., T.O., K.K., K.N., K.S., S.S., S.T., T.A., K.S., S.M., H.S.); and Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (Y.H., Y.O.).
authors.forename: Katsuya
authors.initials: K
authors.lastname: Kozu
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (J.O., K.S., N.K., T.S., R.K., M.N., T.O., K.K., K.N., K.S., S.S., S.T., T.A., K.S., S.M., H.S.); and Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (Y.H., Y.O.).
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Numano
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (J.O., K.S., N.K., T.S., R.K., M.N., T.O., K.K., K.N., K.S., S.S., S.T., T.A., K.S., S.M., H.S.); and Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (Y.H., Y.O.).
authors.forename: Kota
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (J.O., K.S., N.K., T.S., R.K., M.N., T.O., K.K., K.N., K.S., S.S., S.T., T.A., K.S., S.M., H.S.); and Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (Y.H., Y.O.).
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Sunamura
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (J.O., K.S., N.K., T.S., R.K., M.N., T.O., K.K., K.N., K.S., S.S., S.T., T.A., K.S., S.M., H.S.); and Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (Y.H., Y.O.).
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Tatebe
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (J.O., K.S., N.K., T.S., R.K., M.N., T.O., K.K., K.N., K.S., S.S., S.T., T.A., K.S., S.M., H.S.); and Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (Y.H., Y.O.).
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Aoki
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (J.O., K.S., N.K., T.S., R.K., M.N., T.O., K.K., K.N., K.S., S.S., S.T., T.A., K.S., S.M., H.S.); and Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (Y.H., Y.O.).
authors.forename: Koichiro
authors.initials: K
authors.lastname: Sugimura
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (J.O., K.S., N.K., T.S., R.K., M.N., T.O., K.K., K.N., K.S., S.S., S.T., T.A., K.S., S.M., H.S.); and Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (Y.H., Y.O.).
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miyata
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (J.O., K.S., N.K., T.S., R.K., M.N., T.O., K.K., K.N., K.S., S.S., S.T., T.A., K.S., S.M., H.S.); and Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (Y.H., Y.O.).
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hoshikawa
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (J.O., K.S., N.K., T.S., R.K., M.N., T.O., K.K., K.N., K.S., S.S., S.T., T.A., K.S., S.M., H.S.); and Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (Y.H., Y.O.).
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (J.O., K.S., N.K., T.S., R.K., M.N., T.O., K.K., K.N., K.S., S.S., S.T., T.A., K.S., S.M., H.S.); and Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan (Y.H., Y.O.). shimo@cardio.med.tohoku.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000201:enzymology*; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology* / Q000517:prevention & control*; D000860:Hypoxia / Q000201:enzymology* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged
chemical_list: D055372:AMP-Activated Protein Kinases
keywords: cell proliferation; cytokines; inflammation; metformin; pulmonary hypertension