The BMP type II receptor is located in lipid rafts, including caveolae, of pulmonary endothelium in vivo and in vitro

Ramos, M.; Lamé, Michael W.; Segall, H. J.; Wilson, Dennis W

doi:10.1016/j.vph.2005.09.007

Cited by 52 publications

(50 citation statements)

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“…The pAb detected 120-and 75-kDa bands in bovine PAEC, whereas the mAb detected the 25-kDa band in human A549 cells (see Ref. 47 for a discussion of antibody-and cell type-specific differences in the performance of different anti-BMPR2 antibodies). shows that in a per cell basis comparison, increased amounts of Golgi tethers and scaffolding proteins GM130, p115, giantin, and golgin 84, and the SNAREs Vti1a and GS28 were associated with Golgi cisternae within 2 days after MCTP.…”

Section: Resultsmentioning

confidence: 99%

Dysfunction of Golgi tethers, SNAREs, and SNAPs in monocrotaline-induced pulmonary hypertension

Sehgal¹,

Mukhopadhyay²,

Xu³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Monocrotaline (MCT)-induced pulmonary hypertension (PH) in the rat is a widely used experimental model. We have previously shown that MCT pyrrole (MCTP) produces loss of caveolin-1 (cav-1) and endothelial nitric oxide synthase from plasma membrane raft microdomains in pulmonary arterial endothelial cells (PAEC) with the trapping of these proteins in the Golgi organelle (the Golgi blockade hypothesis). In the present study, we investigated the mechanisms underlying this intracellular trafficking block in experiments in cell culture and in the MCT-treated rat. In cell culture, PAEC showed trapping of cav-1 in Golgi membranes as early as 6 h after exposure to MCTP. Phenotypic megalocytosis and a reduction in anterograde trafficking (assayed in terms of the secretion of horseradish peroxidase derived from exogenously transfected expression constructs) were evident within 12 h after MCTP. Cell fractionation and immunofluorescence techniques revealed the marked accumulation of diverse Golgi tethers, soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptors (SNAREs), and soluble NSF attachment proteins (SNAPs), which mediate membrane fusion during vesicular trafficking (GM130, p115, giantin, golgin 84, clathrin heavy chain, syntaxin-4, -6, Vti1a, Vti1b, GS15, GS27, GS28, SNAP23, and ␣-SNAP) in the enlarged/ circumnuclear Golgi in MCTP-treated PAEC and A549 lung epithelial cells. Moreover, NSF, an ATPase required for the "disassembly" of SNARE complexes subsequent to membrane fusion, was increasingly sequestered in non-Golgi membranes. Immunofluorescence studies of lung tissue from MCT-treated rats confirmed enlargement of perinuclear Golgi elements in lung arterial endothelial and parenchymal cells as early as 4 days after MCT. Thus MCTinduced PH represents a disease state characterized by dysfunction of Golgi tethers, SNAREs, and SNAPs and of intracellular vesicular trafficking.soluble N-ethylmaleimide-sensitive factor attachment protein receptors; endothelium; intracellular membrane trafficking; Golgi blockade PULMONARY HYPERTENSION (PH) is a progressive disease with high morbidity and mortality (10). As the clinical manifestations of PH typically occur long after the initial injury, experimental models provide an opportunity to investigate the initiating mechanism at the cellular and biochemical levels (45). Among experimental models of PH, administration of the pyrrolizidine alkaloid monocrotaline (MCT) to the juvenile male rat has and continues to be used extensively (21,29). In this model, progressive PH develops 10 -14 days after a single injection of MCT. The injected MCT is converted to its active pyrrolic derivative [MCT pyrrole (MCTP)] by the cytochrome P-450 system in the liver (36). The bioactive MCTP, which has a short half-life (ϳ3 s in aqueous medium), affects the first vascular bed it encounters: the pulmonary arterial system. The major cellular targets of MCT in the rat lung include the pulmonary arterial endothelial cells (PAEC), pulmonary arterial smooth muscle cells (PASMC), and ...

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Section: Resultsmentioning

confidence: 99%

Dysfunction of Golgi tethers, SNAREs, and SNAPs in monocrotaline-induced pulmonary hypertension

Sehgal¹,

Mukhopadhyay²,

Xu³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…A number of signaling entities that play a role in PAH target to caveolae and/or interact with caveolin-1. These include bone morphogenetic receptor-II [BMPR-II, mutations of which are found in a number of IPAH-patients (164,165)], eNOS, TRPC, reactive oxygen species (ROS), heme-oxygenase-1 (HO-1), serotonin (5HT), and endothelin receptors; it is thus not surprising that altered expression of caveolae/caveolins might increase susceptibility to this disease (37,67,(166)(167)(168)(169). Consistent with data obtained from caveolin-1 KO mice, caveolin-1 expression is reduced in the lungs of patients with IPAH and in animal models of PAH, such as hypoxic-and monocrotaline-treated rats (168, 170-172, F. Murray, R.Y.…”

Section: Caveolins In the Lung: General Principles And A Role In Pulmmentioning

confidence: 99%

“…Injection of caveolin-1 KO mice with an eNOS inhibitor reverses aspects of the PAH phenotype and, thus, loss of the inhibition of eNOS in PAEC may be particularly important for the development of PAH (167). Immunohistochemistry and gradient fractionation of PAEC reveal that BMPR-II and BMP-II-mediated Smad (regulators of transcription that transduce signals from TGFβ receptors) signaling, which may underlie aspects of PAH, localize in caveolae and can interact with caveolin-1 (164,165,169,174). Reduction in caveolin-1 in PAEC after monocrotaline treatment leads to phosphorylation and activation of the transcription factor STAT3, which upregulates proliferative and antiapoptotic genes (171).…”

Section: Caveolins In the Lung: General Principles And A Role In Pulmmentioning

confidence: 99%

Caveolae as Organizers of Pharmacologically Relevant Signal Transduction Molecules

Patel¹,

Murray²,

Insel

2008

Annu. Rev. Pharmacol. Toxicol.

405

363

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Caveolae, a subset of membrane (lipid) rafts, are flask-like invaginations of the plasma membrane that contain caveolin proteins, which serve as organizing centers for cellular signal transduction. Caveolins (-1, -2, and -3) have cytoplasmic N and C termini, palmitolylation sites, and a scaffolding domain that facilitates interaction and organization of signaling molecules so as to help provide coordinated and efficient signal transduction. Such signaling components include upstream entities (e.g., G protein-coupled receptors (GPCRs), receptor tyrosine kinases, and steroid hormone receptors) and downstream components (e.g., heterotrimeric and low-molecularweight G proteins, effector enzymes, and ion channels). Diseases associated with aberrant signaling may result in altered localization or expression of signaling proteins in caveolae. Caveolin-knockout mice have numerous abnormalities, some of which may reflect the impact of total body knockout throughout the life span. This review provides a general overview of caveolins and caveolae, signaling molecules that localize to caveolae, the role of caveolae/caveolin in cardiac and pulmonary pathophysiology, pharmacologic implications of caveolar localization of signaling molecules, and the possibility that caveolae might serve as a therapeutic target.

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“…Smurf-1, which induces ubiquitination and degradation of BMPRII, is upregulated in both MCT and hypoxia models of PH, thus contributing to the reduction in BMPRII expression (86). Interestingly, a part of BMPRII colocalizes with caveolin-1 in caveolae (105). creased association of BMPRII with BMPR1a (13,130).…”

Section: Caveolae and Caveolin-1mentioning

confidence: 99%

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

Mathew

2014

American Journal of Physiology-Heart and Circulatory Physiology

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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...

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The BMP type II receptor is located in lipid rafts, including caveolae, of pulmonary endothelium in vivo and in vitro

Cited by 52 publications

References 52 publications

Dysfunction of Golgi tethers, SNAREs, and SNAPs in monocrotaline-induced pulmonary hypertension

Dysfunction of Golgi tethers, SNAREs, and SNAPs in monocrotaline-induced pulmonary hypertension

Caveolae as Organizers of Pharmacologically Relevant Signal Transduction Molecules

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

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