Chest
Volume 129, Issue 3, March 2006, Pages 696-705
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Original Research: PULMONARY HYPERTENSION
Loss of Caveolin and Heme Oxygenase Expression in Severe Pulmonary Hypertension

https://doi.org/10.1378/chest.129.3.696Get rights and content

Caveolae are cell plasma membrane microdomains implicated in organizing and concentrating many signaling molecules. In the lung, caveolae are in endothelium, smooth muscle, fibroblasts, and pneumocytes. Caveolin is the main structural protein of caveolae. Caveolin 1 is down-regulated in transformed cells and may be a tumor suppressor protein. Caveolin 2 is coexpressed and hetero-oligomerizes with caveolin 1. Because the cells of the plexiform lesions in severe pulmonary hypertension (PH) are phenotypically altered, we wondered whether these cells lack caveolin. We now demonstrate by immunolocalization that while caveolin is expressed in lung endothelial, smooth-muscle, and alveolar septal cells, its expression is absent or decreased in plexiform lesions and in some muscularized precapillary arterioles. In contrast, Western blot analysis of total lung extracts from patients with severe PH shows no significant reduction in caveolin. Similar to the human lung tissue, a rat model of severe PH demonstrates absent-to-decreased caveolin expression in the complex vascular lesions. Additionally, it appears that caveolin and heme oxygenase 1 (HO-1) [a heat shock protein] are co-expressed since HO-1 expression parallels caveolin expression in vascular lesions. We propose that loss of caveolin expression in the cells of the complex vascular lesions in severe PH reflects the proliferating and apoptosis-resistant nature of these cells.

Section snippets

Tissue Samples

Lung tissue was obtained from 14 patients with plexiform pulmonary arteriopathy (clinical diagnosis of severe PH [Table 1]). Ten of the lung specimens were obtained at autopsy, 3 at lung transplant, and 1 at open-lung biopsy. One of the specimens was obtained from lung tissue from a patient with severe PH associated with the use of an anorexigen (dexfenfluramine) and one from a patient with AIDS. “Normal” tissue from four patients with no history of PH was used as a control. Lobectomy was the

Decreased Expression of Caveolin 1 and 2 in the Vascular Lesions of Patients With Severe PH

Caveolin staining was ubiquitous throughout the lung tissue of all patients with primary and secondary PH and in the liver hemangioma. However, the complex vascular structures of severe PH—the plexiform lesions—frequently demonstrated a striking decrease or absence of caveolin 1 and 2 staining (Fig 1, 2), although some of the cells lining the residual lumens stained positive for caveolin (Fig 2). When serial sections were stained using antibodies against Factor VIII-r.ag, α-SMA, and caveolin 1,

Discussion

Exuberant endothelial cell growth has been described in the lungs from patients with severe PH.18 The elucidation of the mechanisms involved in the control of endothelial cell proliferation is fundamentally important in the pathogenesis of severe PH31 and has recently received increased attention.22, 31, 32, 33

Endothelial cells are a major cell type in the lung tissue and normally express high levels of caveolin 1.34 Caveolin 1 and 2 null animal lungs are markedly abnormal with thickened

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    This work is supported by RO1 HL60913–01 (Dr. Voelkel) and K08 HL03911–04 (Dr. Cool) from the Heart, Lung, and Blood Institute, National Institutes of Health.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

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