Loss of Caveolin and Heme Oxygenase Expression in Severe Pulmonary Hypertension: Conclusion

Previous work has shown that differentiated contractile smooth-muscle cells found in the normal arterial media express plasma membrane caveolae in a several-fold-higher density than the synthetic smooth-muscle cells that appear in the neointima after vascular injury. In addition, the handling of lipoprotein-derived cholesterol is also changed, since cholesterol is preferentially associated with caveolae on the surface of contractile smooth-muscle cells and is more randomly dispersed over the surface of noncontractile synthetic smooth cells. Therefore, one consequence of loss of caveolae and presumably decreased caveolin expression is an impaired uptake and transport of cholesterol. Via H-Ras, a critical connection has been established between caveolin in cholesterol trafficking and cell signaling. Knockout mice deficient in caveolin display uncontrolled proliferation of lung endothelial cells and fibroblasts. Here

Although the etiology of the caveolin 1    null phenotype is unclear, an assessment of endothelial cell function in aortic ring experiments” shows decreased vasoconstriction due to uninhibited nitric oxide production (a result which is consistent with the known inhibitory effect of caveolin 1 on endothelial nitric oxide synthase). The previously described strong endothelial nitric oxide synthase expression in plexiform lesions of severe PH40 may be due to decreased caveolin 1 expression. Caveolin 2    null mice, while demonstrating the lung parenchymal septal thickening and endothelial cell hyperplasia of the caveolin 1 null mice, do not show the abnormal vascular responses or altered lipid metabolism of the caveolin 1 null mice, indicating a possible specific pulmonary role for caveolin 2. Caveolin 2 expression is also decreased in the caveo-lin 1 null mice, further support for a pulmonary-specific role. At present, the functional importance of decreased caveolin expression in severe PH remains unclear, but the markedly reduced caveolin 1 and 2 expression in plexiform lesions provides another marker of the altered endothelial and vascular smooth-muscle cell phenotypes in the lungs of patients with severe PH.

This entry was posted in Pulmonary Function and tagged caveolin, heme oxygenase 1, pulmonary hypertension.