title: Mitigation of tight junction protein dysfunction in lung microvascular endothelial cells with pitavastatin.
abstract: Statin use in individuals with chronic obstructive pulmonary disease (COPD) with coexisting cardiovascular disease is associated with a reduced risk of exacerbations. The mechanisms by which statin plays a role in the pathophysiology of COPD have not been defined. To explore the mechanisms involved, we investigated the effect of statin on endothelial cell function, especially endothelial cell tight junctions.
  
  
  
  We primarily assessed whether pitavastatin could help mitigate the development of emphysema induced by continuous cigarette smoking (CS) exposure. We also investigated the activation of liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling, which plays a role in maintaining endothelial functions, important tight junction proteins, zonula occludens (ZO)-1 and claudin-5 expression, and lung microvascular endothelial cell permeability.
  
  
  
  We found that pitavastatin prevented the CS-induced decrease in angiomotin-like protein 1 (AmotL1)-positive vessels via the activation of LKB1/AMPK signaling and IFN-γ-induced hyperpermeability of cultured human lung microvascular endothelial cells by maintaining the levels of AmotL1, ZO-1, and claudin-5 expression at the tight junctions.
  
  
  
  Our results indicate that the maintenance of lung microvascular endothelial cells by pitavastatin prevents tight junction protein dysfunctions induced by CS. These findings may ultimately lead to new and novel therapeutic targets for patients with COPD.
authors.affiliation: Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, 0208505, Japan. Electronic address: m38_riotos@yahoo.co.jp.
authors.forename: Rioto
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, 0208505, Japan. Electronic address: ICB75097@nifty.com.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, 0208505, Japan. Electronic address: shinji6311chiba@yahoo.co.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Chiba
authors.affiliation: Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, 0208505, Japan. Electronic address: tmizuno1004@gmail.com.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Mizuno
authors.affiliation: Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, 0208505, Japan. Electronic address: anything3137@gmail.com.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Abe
authors.affiliation: Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, 0208505, Japan. Electronic address: m06092yh@jichi.ac.jp.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Horii
authors.affiliation: Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, 0208505, Japan. Electronic address: all-checker1983@m7.dion.ne.jp.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nagashima
authors.affiliation: Department of Thoracic Surgery, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, 0208505, Japan. Electronic address: ttanita@iwate-med.ac.jp.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Tanita
authors.affiliation: Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, 0208505, Japan. Electronic address: kyamauch@iwate-med.ac.jp.
authors.forename: Kohei
authors.initials: K
authors.lastname: Yamauchi
mesh_terms: D000091304:Angiopoietin-Like Protein 1; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D011656:Pulmonary Emphysema / Q000209:etiology / Q000517:prevention & control*; D011804:Quinolines / Q000494:pharmacology*; D012907:Smoking / Q000009:adverse effects; D062725:Tight Junction Proteins / Q000187:drug effects* / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism
chemical_list: C449807:Amotl1 protein, mouse; D000091304:Angiopoietin-Like Protein 1; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011804:Quinolines; D062725:Tight Junction Proteins; C108475:pitavastatin
keywords: AmotL1; COPD; Exacerbation; Statin; Tight junction