title: Increased smooth muscle cell expression of caveolin-1 and caveolae contribute to the pathophysiology of idiopathic pulmonary arterial hypertension.
abstract: Vasoconstriction and vascular medial hypertrophy, resulting from increased intracellular [Ca2+] in pulmonary artery smooth muscle cells (PASMC), contribute to elevated vascular resistance in patients with idiopathic pulmonary arterial hypertension (IPAH). Caveolae, microdomains within the plasma membrane, contain the protein caveolin, which binds certain signaling molecules. We tested the hypothesis that PASMC from IPAH patients express more caveolin-1 (Cav-1) and caveolae, which contribute to increased capacitative Ca2+ entry (CCE) and DNA synthesis. Immunohistochemistry showed increased expression of Cav-1 in smooth muscle cells but not endothelial cells of pulmonary arteries from patients with IPAH. Subcellular fractionation and electron microscopy confirmed the increase in Cav-1 and caveolae expression in IPAH-PASMC. Treatment of IPAH-PASMC with agents that deplete membrane cholesterol (methyl-beta-cyclodextrin or lovastatin) disrupted caveolae, attenuated CCE, and inhibited DNA synthesis of IPAH-PASMC. Increasing Cav-1 expression of normal PASMC with a Cav-1-encoding adenovirus increased caveolae formation, CCE, and DNA synthesis; treatment of IPAH-PASMC with siRNA targeted to Cav-1 produced the opposite effects. Treatments that down-regulate caveolin/caveolae expression, including cholesterol-lowering drugs, reversed the increased CCE and DNA synthesis in IPAH-PASMC. Increased caveolin and caveolae expression thus contribute to IPAH-PASMC pathophysiology. The close relationship between caveolin/caveolae expression and altered cell physiology in IPAH contrast with previous results obtained in various animal models, including caveolin-knockout mice, thus emphasizing unique features of the human disease. The results imply that disruption of caveolae in PASMC may provide a novel therapeutic approach to attenuate disease manifestations of IPAH.
authors.affiliation: University of California, San Diego, Department of Pharmacology, 9500 Gilman Dr., La Jolla, CA 92093-0636, USA.
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
authors.forename: Shen
authors.initials: S
authors.lastname: Zhang
authors.forename: Fiona
authors.initials: F
authors.lastname: Murray
authors.forename: Ryan Y S
authors.initials: RY
authors.lastname: Suda
authors.forename: Brian P
authors.initials: BP
authors.lastname: Head
authors.forename: Utako
authors.initials: U
authors.lastname: Yokoyama
authors.forename: James S
authors.initials: JS
authors.lastname: Swaney
authors.forename: Ingrid R
authors.initials: IR
authors.lastname: Niesman
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Soni Savai
authors.initials: SS
authors.lastname: Pullamsetti
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Thistlethwaite
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyanohara
authors.forename: Marilyn G
authors.initials: MG
authors.lastname: Farquhar
authors.forename: Jason X-J
authors.initials: JX
authors.lastname: Yuan
authors.forename: Paul A
authors.initials: PA
authors.lastname: Insel
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D021941:Caveolae / Q000378:metabolism* / Q000473:pathology; D051242:Caveolin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D015151:Immunoblotting; D008148:Lovastatin / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D011651:Pulmonary Artery / Q000503:physiopathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D050052:TRPC Cation Channels / Q000235:genetics
chemical_list: D051242:Caveolin 1; D034741:RNA, Small Interfering; D050052:TRPC Cation Channels; D008148:Lovastatin; D002118:Calcium