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

Hemal H. Patel^*,1, Shen Zhang^,1, Fiona Murray^*,1, 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 X.-J. Yuan and Paul A. Insel^*,,2

Departments of
^* Pharmacology,

Medicine,

Cellular and Molecular Medicine,

^|| Surgery, and

^¶ Gene Therapy Program,

Pathology, University of California, San Diego, La Jolla, California, USA; and

University of Giessen Lung Center, Medical Clinic II/V, Giessen, Germany

²Correspondence: University of California, San Diego, Department of Pharmacology, 9500 Gilman Dr., BSB 3076, La Jolla, CA 92093-0636, USA. E-mail: pinsel{at}ucsd.edu

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-ß-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.—Patel, H. H., Zhang, S., Murray, F., Suda, R. Y. S., Head, B. P., Yokoyama, U., Swaney, J. S., Niesman, I. R., Schermuly, R. T., Savai Pullamsetti, S., Thistlethwaite, P. A., Miyanohara, A., Farquhar, M. G., Yuan, J. X.-J., Insel, P. A. Increased smooth muscle cell expression of caveolin-1 and caveolae contribute to the pathophysiology of idiopathic pulmonary arterial hypertension.

Key Words: statins • calcium • primary pulmonary hypertension • secondary pulmonary hypertension

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