Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice

Abstract

Caveolins are important components of caveolae, which have been implicated in vesicular trafficking and signal transduction. To investigate the in vivo significance of Caveolins in mammals, we generated mice deficient in the caveolin-1 (cav-1) gene and have shown that, in the absence of Cav-1, no caveolae structures were observed in several nonmuscle cell types. Although cav-1 ؊/؊ mice are viable, histological examination and echocardiography identified a spectrum of characteristics of dilated cardiomyopathy in the left ventricular chamber of the cav-1-deficient hearts, including an enlarged ventricular chamber diameter, thin posterior wall, and decreased contractility. These animals also have marked right ventricular hypertrophy, suggesting a chronic increase in pulmonary artery pressure. Direct measurement of pulmonary artery pressure and histological analysis revealed that the cav-1 ؊/؊ mice exhibit pulmonary hypertension, which may contribute to the right ventricle hypertrophy. In addition, the loss of Cav-1 leads to a dramatic increase in systemic NO levels. Our studies provided in vivo evidence that cav-1 is essential for the control of systemic NO levels and normal cardiopulmonary function.

Caveolin-1: a critical regulator of pulmonary vascular architecture and nitric oxide bioavailability in pulmonary hypertension

“…Despite systemic hypotension, cav-1 Ϫ/Ϫ animals develop significant pulmonary hypertension and associated increases in pulmonary artery pressure and right ventricular hypertrophy as described in this issue of AJP-Lung by Maniatis et al (11) and by others (4,17,23). Endothelial cell-specific reconstitution of cav-1 expression in cav-1 Ϫ/Ϫ mice restored the pulmonary and vascular defects observed in these animals, as evident by the reversal of the pulmonary hypertension and cardiac hypertrophy (12).…”

“…Significant cardiac defects were observed in cav-1 Ϫ/Ϫ mice including increased right ventricular volume and hypertrophy, left ventricular wall thickening, loss of systolic function, and evidence of cardiac fibrosis (2,4,22). The lungs of cav-1 Ϫ/Ϫ mice display a thickening of the parenchyma and alveolar septae resulting from bronchial and alveolar epithelial cell hyperproliferation (12, 17), evidence of endothelial cell proliferation (17), and pulmonary fibrosis (4).Despite systemic hypotension, cav-1 Ϫ/Ϫ animals develop significant pulmonary hypertension and associated increases in pulmonary artery pressure and right ventricular hypertrophy as described in this issue of AJP-Lung by Maniatis et al (11) and by others (4, 17,23). Endothelial cell-specific reconstitution of cav-1 expression in cav-1 Ϫ/Ϫ mice restored the pulmonary and vascular defects observed in these animals, as evident by the reversal of the pulmonary hypertension and cardiac hypertrophy (12).…”

Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity

“…Caveolin-1 Ϫ/Ϫ mice are viable but with shortened life span (106). These mice exhibit hypercellular lung phenotypes, cardiomyopathy, systemic vasculopathy, and PH (27,90,136). In these mice, loss of caveolin-1 is associated with hyperactivation of eNOS, increased cGMP production, and uncoupling of eNOS, leading to the generation of reactive oxygen species (ROS) and nitrogen species.…”

Atrial fibrillation: the role of common and rare genetic variants

“…32 CAV1 knockout mice develop dilated cardiomyopathy and pulmonary hypertension. 33 The SNP rs3903239 is located on chromosome 1q24, 46-kb upstream from the closest gene PRRX1 encoding a homeodomain transcription factor highly expressed in the developing heart. 18 Knock-out mouse models have revealed that PRRX1 is necessary for the normal development of great vessels and lung vascularization.…”