Increased smooth muscle cell expression of caveolin-1 and caveolae contribute to the pathophysiology of idiopathic pulmonary arterial hypertension

Hemal H. Patel, Shen Zhang, Fiona Murray, Ryan Y S Suda, Brian P. Head, Utako Yokoyama, James S. Swaney, Ingrid R. Niesman, Ralph T. Schermuly, Soni Savai Pullamsetti, Patricia A. Thistlethwaite, Atsushi Miyanohara, Marilyn G. Farquhar, Jason Yuan, Paul A. Insel

Research output: Contribution to journalArticle

88 Citations (Scopus)

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 IPAHPASMC with agents that deplete membrane cholesterol (methyl-β-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.

Original languageEnglish (US)
Pages (from-to)2970-2979
Number of pages10
JournalFASEB Journal
Volume21
Issue number11
DOIs
StatePublished - Sep 2007
Externally publishedYes

Fingerprint

Caveolin 1
Caveolae
pulmonary artery
pathophysiology
smooth muscle
myocytes
Pulmonary Artery
hypertension
Smooth Muscle Myocytes
Muscle
lungs
Cells
Caveolins
calcium
synthesis
DNA
blood vessels
idiopathic diseases
Cholesterol
cholesterol

Keywords

  • Calcium
  • Primary pulmonary hypertension
  • Secondary pulmonary hypertension
  • Statins

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Increased smooth muscle cell expression of caveolin-1 and caveolae contribute to the pathophysiology of idiopathic pulmonary arterial hypertension. / Patel, Hemal H.; Zhang, Shen; Murray, Fiona; Suda, Ryan Y S; Head, Brian P.; Yokoyama, Utako; Swaney, James S.; Niesman, Ingrid R.; Schermuly, Ralph T.; Pullamsetti, Soni Savai; Thistlethwaite, Patricia A.; Miyanohara, Atsushi; Farquhar, Marilyn G.; Yuan, Jason; Insel, Paul A.

In: FASEB Journal, Vol. 21, No. 11, 09.2007, p. 2970-2979.

Research output: Contribution to journalArticle

Patel, HH, Zhang, S, Murray, F, Suda, RYS, Head, BP, Yokoyama, U, Swaney, JS, Niesman, IR, Schermuly, RT, Pullamsetti, SS, Thistlethwaite, PA, Miyanohara, A, Farquhar, MG, Yuan, J & Insel, PA 2007, 'Increased smooth muscle cell expression of caveolin-1 and caveolae contribute to the pathophysiology of idiopathic pulmonary arterial hypertension', FASEB Journal, vol. 21, no. 11, pp. 2970-2979. https://doi.org/10.1096/fj.07-8424com
Patel, Hemal H. ; Zhang, Shen ; Murray, Fiona ; Suda, Ryan Y S ; Head, Brian P. ; Yokoyama, Utako ; Swaney, James S. ; Niesman, Ingrid R. ; Schermuly, Ralph T. ; Pullamsetti, Soni Savai ; Thistlethwaite, Patricia A. ; Miyanohara, Atsushi ; Farquhar, Marilyn G. ; Yuan, Jason ; Insel, Paul A. / Increased smooth muscle cell expression of caveolin-1 and caveolae contribute to the pathophysiology of idiopathic pulmonary arterial hypertension. In: FASEB Journal. 2007 ; Vol. 21, No. 11. pp. 2970-2979.
@article{8077f7738ae440b3bdf449dda1532def,
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 IPAHPASMC with agents that deplete membrane cholesterol (methyl-β-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.",
keywords = "Calcium, Primary pulmonary hypertension, Secondary pulmonary hypertension, Statins",
author = "Patel, {Hemal H.} and Shen Zhang and Fiona Murray and Suda, {Ryan Y S} and Head, {Brian P.} and Utako Yokoyama and Swaney, {James S.} and Niesman, {Ingrid R.} and Schermuly, {Ralph T.} and Pullamsetti, {Soni Savai} and Thistlethwaite, {Patricia A.} and Atsushi Miyanohara and Farquhar, {Marilyn G.} and Jason Yuan and Insel, {Paul A.}",
year = "2007",
month = "9",
doi = "10.1096/fj.07-8424com",
language = "English (US)",
volume = "21",
pages = "2970--2979",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "11",

}

TY - JOUR

T1 - Increased smooth muscle cell expression of caveolin-1 and caveolae contribute to the pathophysiology of idiopathic pulmonary arterial hypertension

AU - Patel, Hemal H.

AU - Zhang, Shen

AU - Murray, Fiona

AU - Suda, Ryan Y S

AU - Head, Brian P.

AU - Yokoyama, Utako

AU - Swaney, James S.

AU - Niesman, Ingrid R.

AU - Schermuly, Ralph T.

AU - Pullamsetti, Soni Savai

AU - Thistlethwaite, Patricia A.

AU - Miyanohara, Atsushi

AU - Farquhar, Marilyn G.

AU - Yuan, Jason

AU - Insel, Paul A.

PY - 2007/9

Y1 - 2007/9

N2 - 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 IPAHPASMC with agents that deplete membrane cholesterol (methyl-β-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.

AB - 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 IPAHPASMC with agents that deplete membrane cholesterol (methyl-β-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.

KW - Calcium

KW - Primary pulmonary hypertension

KW - Secondary pulmonary hypertension

KW - Statins

UR - http://www.scopus.com/inward/record.url?scp=34548484104&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34548484104&partnerID=8YFLogxK

U2 - 10.1096/fj.07-8424com

DO - 10.1096/fj.07-8424com

M3 - Article

C2 - 17470567

AN - SCOPUS:34548484104

VL - 21

SP - 2970

EP - 2979

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 11

ER -