Chest
Original Research: PULMONARY HYPERTENSIONLoss of Caveolin and Heme Oxygenase Expression in Severe Pulmonary Hypertension
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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Cited by (89)
Defining the clinical validity of genes reported to cause pulmonary arterial hypertension
2023, Genetics in MedicineVascular pathobiology of pulmonary hypertension
2023, Journal of Heart and Lung TransplantationCitation Excerpt :There are discrepancies among studies as to the expression of the endothelial isoform of NOS (eNOS) in lungs of patients with PAH, and importantly, eNOS levels may not reflect those of NO as the enzyme can become uncoupled, producing superoxide.33 In eNOS(-/-) mice, mild hypoxia results in severe PH whereas intratracheal delivery of an adenoviral vector encoding the eNOS gene attenuates hypoxia-induced PH.36,37 Caveolin1 is a major component of caveolae, and Cav-1 deficiency in mice results in chronic activation of eNOS and formation of peroxynitrite which induces vasoconstriction, pulmonary vascular remodeling and thereby, PH.38,39 Caveolin1 levels are downregulated in PAECs of rats with monocrotaline-induced PH and in PAH patients, are low in plexiform lesions compared to the rest of the lung.40,41 Interestingly, frameshift mutations in CAV1 are associated in rare cases with PAH and with reduced anti-caveolin1 staining in ECs of small arterioles of the lung.42
Pulmonary artery hypertension in childhood: The transforming growth factor-β superfamily-related genes
2018, Pediatrics and NeonatologyCaveolin and Endothelial NO Signaling
2018, Current Topics in MembranesCitation Excerpt :In addition, Cav-1−/− mice also develop PH (Maniatis et al., 2008; Wunderlich et al., 2006; Zhao et al., 2002) which can be rescued by restoring Cav-1 expression in the endothelium (Murata et al., 2007). The decrease in endothelial cell Cav-1 expression in the lungs of patients with class I PH was primarily observed in plexiform lesions, where endothelial cells were found to be hyperproliferative (Achcar et al., 2006). Prolonged treatment of Cav-1−/− mice from birth with the NOS inhibitor L-NAME completely reversed pathological pulmonary vascular changes as well as PH and right heart hypertrophy.
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).