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

Abstract

Mathew R. Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity. Am J Physiol Heart Circ Physiol 306: H15-H25, 2014. First published October 25, 2013 doi:10.1152/ajpheart.00266.2013.-Pulmonary hypertension (PH) is a progressive disease with a high morbidity and mortality rate. Despite important advances in the field, the precise mechanisms leading to PH are not yet understood. Main features of PH are loss of vasodilatory response, the activation of proliferative and antiapoptotic pathways leading to pulmonary vascular remodeling and obstruction, elevated pressure and right ventricular hypertrophy, resulting in right ventricular failure and death. Experimental studies suggest that endothelial dysfunction may be the key underlying feature in PH. Caveolin-1, a major protein constituent of caveolae, interacts with several signaling molecules including the ones implicated in PH and modulates them. Disruption and progressive loss of endothelial caveolin-1 with reciprocal activation of proliferative pathways occur before the onset of PH, and the rescue of caveolin-1 inhibits proliferative pathways and attenuates PH. Extensive endothelial damage/loss occurs during the progression of the disease with subsequent enhanced expression of caveolin-1 in smooth muscle cells. This caveolin-1 in smooth muscle cells switches from being an antiproliferative factor to a proproliferative one and participates in cell proliferation and cell migration, possibly leading to irreversible PH. In contrast, the disruption of endothelial caveolin-1 is not observed in the hypoxia-induced PH, a reversible form of PH. However, proliferative pathways are activated in this model, indicating caveolin-1 dysfunction. Thus disruption or dysfunction of endothelial caveolin-1 leads to PH, and the status of caveolin-1 may determine the reversibility versus irreversibility of PH. This article reviews the role of caveolin-1 and cell membrane integrity in the pathogenesis and progression of PH.caveolin-1; endothelial cells; pulmonary hypertension; smooth muscle cells THIS ARTICLE is part of a collection on Pathophysiology of Hypertension. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology.org/.In 1891, Ernst von Romberg, a German physician, described histological changes in pulmonary hypertension (PH) as pulmonary vascular sclerosis (30). Since then remarkable advances have been made in the understanding of PH, but the pathogenesis of PH still remains elusive, partly because a number of diseases can lead to PH and multiple signaling pathways are implicated in PH. Furthermore, not all signaling pathways are activated in a given patient, and their activation may depend on the stage of the disease. Experimental data suggest that the vascular changes occur before the onset of PH (47,48). Therefore, it is not surprising that by the time the diagnosis of PH is made, most patients have significant pathological changes in pulmonary vasculatu...

Increase in caveolae and caveolin-1 expression modulates agonist-induced contraction and store- and receptor-operated Ca2+ entry in pulmonary arteries of pulmonary hypertensive rats

“…Cav-1 interacts with a variety of signaling proteins through specific binding of the 20 amino-acid Cav-1-scaffolding domain [32][33][34]. It is involved in many cardiovascular diseases including atherosclerosis [46,47], and play an important role in the development of PH [48]. Original studies using Cav-1 null mice showed that deletion of the Cav-1 gene causes a marked reduction in life span due to a combination of cardiac hypertrophy, structural defects in the lungs and PH [39,49,50].…”

Salvianolic acid A attenuates vascular remodeling in a pulmonary arterial hypertension rat model

“…Pulmonary arterial hypertension (PAH) is characterized by dysregulated pulmonary vascular remodeling, which leads to an increase in pulmonary vascular resistance, right ventricular hypertrophy, uncompensated right heart failure, and ultimate death [1,2] . Despite the current therapeutic approaches for improving symptoms, exercise capacity, and hemodynamic variables, these therapies have a limited effect on vascular remodeling and do not confer a mortality benefit [3,4] .…”

Asymmetric dimethyl arginine induces pulmonary vascular dysfunction via activation of signal transducer and activator of transcription 3 and stabilization of hypoxia-inducible factor 1-alpha

“…These factors contribute to development of endothelial dysfunction and progression of vascular remodeling by instigating the proliferation and migration of vascular SMC. This vascular pathology can be triggered by genetic and environmental stimuli, including hypoxia [1,8,9].…”