Critical Role of Caveolin-1 Loss/Dysfunction in Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) is a rare disease with a high morbidity and mortality rate. A number of systemic diseases and genetic mutations are known to lead to PH. The main features of PH are altered vascular relaxation responses and the activation of proliferative and anti-apoptotic pathways, resulting in pulmonary vascular remodeling, elevated pulmonary artery pressure, and right ventricular hypertrophy, ultimately leading to right heart failure and premature death. Important advances have been made in the field of pulmonary pathobiology, and several deregulated signaling pathways have been shown to be associated with PH. Clinical and experimental studies suggest that, irrespective of the underlying disease, endothelial cell disruption and/or dysfunction play a key role in the pathogenesis of PH. Endothelial caveolin-1, a cell membrane protein, interacts with and regulates several transcription factors and maintains homeostasis. Disruption of endothelial cells leads to the loss or dysfunction of endothelial caveolin-1, resulting in reciprocal activation of proliferative and inflammatory pathways, leading to cell proliferation, medial hypertrophy, and PH, which initiates PH and facilitates its progression. The disruption of endothelial cells, accompanied by the loss of endothelial caveolin-1, is accompanied by enhanced expression of caveolin-1 in smooth muscle cells (SMCs) that leads to pro-proliferative and pro-migratory responses, subsequently leading to neointima formation. The neointimal cells have low caveolin-1 and normal eNOS expression that may be responsible for promoting nitrosative and oxidative stress, furthering cell proliferation and metabolic alterations. These changes have been observed in human PH lungs and in experimental models of PH. In hypoxia-induced PH, there is no endothelial disruption, loss of endothelial caveolin-1, or enhanced expression of caveolin-1 in SMCs. Hypoxia induces alterations in membrane composition without caveolin-1 or any other membrane protein loss. However, caveolin-1 is dysfunctional, resulting in cell proliferation, medial hypertrophy, and PH. These alterations are reversible upon removal of hypoxia, provided there is no associated EC disruption. This review examined the role of caveolin-1 disruption and dysfunction in PH.

The Cavin-1/Caveolin-1 interaction attenuates BMP/Smad signaling in pulmonary hypertension by interfering with BMPR2/Caveolin-1 binding

“…Hypoxia plays a pivotal role in the pathogenesis of pulmonary hypertension 20,21 and induces PAECs dysfunction, apoptosis, and the activation of in ammatory and proliferative pathways 22,23 . Apoptosisresistant proliferating PAECs are involved in the onset of pulmonary hypertension 24 .…”

Long-term administration of Western diet induced metabolic syndrome in mice and causes cardiac microvascular dysfunction, cardiomyocyte mitochondrial damage, and cardiac remodeling involving caveolae and caveolin-1 expression

“…CAV-1 regulates intracellular lipid transport by binding with free cholesterol, glycolipids, and fatty acids, in the ER, Golgi, mitochondria, and caveolae. Previous studies have demonstrated that CAV-1 regulates the permeability of vascular interendothelial junctions and the expression of VE-Cadherin and β-catenin, and mediates vascular endothelial permeability and endothelial barrier dysfunction [ 39 , 40 ]. Our results showed that Western diet-induced MS significantly increased the expression of caveolae and CAV-1 in the vascular endothelial cells, enhanced CAV-1 and eNOS interaction, increased the CAV-1 and lipid droplets binding efficiency, and reduced endothelial adhesion molecular expression.…”

Screening of the Key Genes and Signaling Pathways for Schizophrenia Using Bioinformatics and Next Generation Sequencing Data Analysis

“…CDKN2A [226], CAV1 [472] and CD40 [445] are involved in the mediation of obesity. The results showed that CDKN2A [105], CAV1 [534], BTK (Bruton tyrosine kinase) [561] and CD40 [505] were expressed in hypertension. CAV1 [303] and IRS4 [317] expression is significantly regulated in schizophrenia patients.…”