Short-Term Administration of a Cell-Permeable Caveolin-1 Peptide Prevents the Development of Monocrotaline-Induced Pulmonary Hypertension and Right Ventricular Hypertrophy

Jasmin, Jean François; Mercier, Isabelle Le; Dupuis, Jocelyn; Tanowitz, Herbert B.; Lisanti, Michael P.

doi:10.1161/circulationaha.106.634709

Cited by 94 publications

(86 citation statements)

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“…Close examination of individual cells in vivo showed that the specific endothelial cells that had a loss of cav-1 expression were the same cells with hyperactivation of PY-STAT3 and increased DNA synthesis (24). This reciprocal relationship between cav-1 downregulation and PY-STAT3 activation in PAH in the rat/MCT model was later confirmed by Jasmin and colleagues (19). That the increase in PY-STAT3 levels was seen before the onset of PAH in MCT-treated rats (19,24) and that the introduction of a cav-1 scaffolding domain peptide blocked PY-STAT3 hyperactivation and ameliorated indicated that STAT3 played a role in Address for reprint requests and other correspondence: P. B. Sehgal, Rm.…”

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confidence: 54%

“…This reciprocal relationship between cav-1 downregulation and PY-STAT3 activation in PAH in the rat/MCT model was later confirmed by Jasmin and colleagues (19). That the increase in PY-STAT3 levels was seen before the onset of PAH in MCT-treated rats (19,24) and that the introduction of a cav-1 scaffolding domain peptide blocked PY-STAT3 hyperactivation and ameliorated MCT-induced PAH (19) indicated that STAT3 played a role in the initiation of PAH, at least in this animal model. Moreover, Park and colleagues (33) reported the hyperactivation of PY-STAT3 in lungs of cav-1 Ϫ/Ϫ mice, which spontaneously developed PAH.…”

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confidence: 54%

“…Second, whereas cav-1 is a negative regulator of STAT3 tyrosine phosphorylation at the plasma membrane lipid raft level (see Ref. 19 and citations therein for details of how cav-1 negatively regulates signaling at the plasma membrane), the effect of the interaction of STAT3 with cav-1 at other subcellular compartments (like endosomes) is likely different and not known. Third, from work in this laboratory in the MCT model of PAH, the downregulation of cav-1 seen at the whole cell level is largely representative of a loss of cav-1 from the plasma membrane rafts/caveolae (24).…”

Section: Discussionmentioning

confidence: 99%

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Cytoplasmic provenance of STAT3 and PY-STAT3 in the endolysosomal compartments in pulmonary arterial endothelial and smooth muscle cells: implications in pulmonary arterial hypertension

Mukhopadhyay

Shah

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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PB. Cytoplasmic provenance of STAT3 and PY-STAT3 in the endolysosomal compartments in pulmonary arterial endothelial and smooth muscle cells: implications in pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 294: L449-L468, 2008. First published December 14, 2007 doi:10.1152/ajplung.00377.2007.-Lung vascular lesions in pulmonary arterial hypertension (PAH) are characterized by enlarged, vacuolated ("megalocytotic") pulmonary arterial endothelial (PAEC) and smooth muscle cells (PASMC). We have recently proposed that dysfunction of vesicle tethers, soluble N-ethylmaleimide-sensitive factor attachment proteins (SNAPs), and SNAP receptors (SNAREs), leading to disruptions of intracellular trafficking in the Golgi to plasma membrane (centrifugal) and the plasma membrane to cell interior (centripetal) directions is a key causal mechanism in this disease. In PAH, there was a reciprocal relationship between loss of caveolin-1 (cav-1) in PAECs and increased expression of "activated" tyrosine-phosphorylated STAT3 (PY-STAT3) associated with a block in centrifugal trafficking to/through the Golgi organelle. In the present study, we investigated 1) whether centripetal trafficking of STAT3 and PY-STAT3 in PAECs and PASMCs was membrane-associated, and 2) whether this might be affected in PAH. Immunofluorescence and live cell imaging studies showed that, in both PAEC and PASMC, STAT3 was associated with cytoplasmic vesicles partially colocalizing with markers of the endolysosomal compartments (clathrin, EEA1, Rab5, Rab11, and LAMP1). Overexpression of cav-1 increased the targeting of STAT3 to lysosomes and inhibited STAT3 transcriptional activity. Exposure of PAECs to monocrotaline (MCT) pyrrole, which causes PAH in the rat, led to a loss of caveolar STAT3 with increased sequestration of STAT3 and PY-STAT3 in endosomes. In vivo, marked cytoplasmic sequestration of activated PY-STAT3 was a common feature in PAEC in the rat/MCT model and in cells in the proliferative arterial and plexiform lesions in PAH in humans. These data highlight the epigenetic regulation of centripetal cytokine and growth-factor signaling pathways and its modulation in PAH.caveolin-1; signaling endosome; monocrotaline PULMONARY ARTERIAL HYPERTENSION (PAH) is characterized by the reduction of the lumen of medium-sized pulmonary arteries by proliferating, enlarged, vacuolated, and apoptosis-resistant ("megalocytotic") pulmonary arterial endothelial (PAEC) and smooth muscle (PASMC) cells (42,43). We (24, 26 -28, 41-43, 47) recently proposed that dysfunction of vesicle tethers, soluble N-ethylmaleimide-sensitive factor attachment proteins (SNAPs), and SNAP receptors (SNAREs), leading to disruptions of intracellular trafficking from the Golgi to plasma membrane (centrifugal) and the plasma membrane to cell interior (centripetal) directions might represent a key subcellular mechanism leading to the changes observed in endothelial and vascular smooth muscle cells in PAH. We (24, 26 -28, 41-43, 47) have previously provided evidence for disrupt...

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confidence: 54%

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confidence: 54%

Section: Discussionmentioning

confidence: 99%

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Cytoplasmic provenance of STAT3 and PY-STAT3 in the endolysosomal compartments in pulmonary arterial endothelial and smooth muscle cells: implications in pulmonary arterial hypertension

Mukhopadhyay

Shah

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The downstream effects of PY-STAT3 are mediated by cyclin D1 (cell cycle regulator), survivin and B-cell lymphoma-extra large (Bcl-xL) (antiapoptotic factors), all reported to be upregulated in PH. Inhibition of STAT3 reduces the expression of cyclin D1, survivin, and Bcl-xL (36,60) and prevents neointima formation in the carotid artery injury model (116). Caveolin-1 acts as a suppressor of cytokine signaling and inhibits PY-STAT3 activation and modulates proinflammatory cytokines (61).…”

Section: Caveolae and Caveolin-1mentioning

confidence: 99%

“…In the MCT model, progressive loss of endothelial caveolin-1 and the activation of proliferative and antiapoptotic pathways occur before the onset of PH (48,78). The rescue of caveolin-1 inhibits the proliferative pathways (PY-STAT3, cyclin D1 and D3) and attenuates PH (47,60). Studies with caveolin-1 Ϫ/Ϫ mice have further underscored the importance of caveolin-1 in vascular health and disease.…”

Section: Disruption Of Ec Membranementioning

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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Decreased expression of caveolin 1 in patients with systemic sclerosis: Crucial role in the pathogenesis of tissue fibrosis

Galdo

Sotgia

Almeida

et al. 2008

Arthritis & Rheumatism

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Objective. Recent studies have implicated caveolin 1 in the regulation of transforming growth factor ␤ (TGF␤) downstream signaling. Given the crucial role of TGF␤ in the pathogenesis of systemic sclerosis (SSc), we sought to determine whether caveolin 1 is also involved in the pathogenesis of tissue fibrosis in SSc. We analyzed the expression of CAV1 in affected SSc tissues, studied the effects of lack of expression of CAV1 in vitro and in vivo, and analyzed the effects of restoration of caveolin 1 function on the fibrotic phenotype of SSc fibroblasts in vitro.Methods. CAV1 expression in tissues was analyzed by immunofluorescence and confocal microscopy. The extent of tissue fibrosis in Cav1-knockout mice was assessed by histologic/histochemical analyses and quantified by hydroxyproline assays. Cav1-null and SSc fibroblast phenotypes and protein production were analyzed by real-time polymerase chain reaction, immunofluorescence, Western blot, and multiplexed enzymelinked immunosorbent assay techniques. The effects of restoration of caveolin 1 function in SSc fibroblasts in vitro were also examined using a cell-permeable recombinant CAV1 peptide.

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Short-Term Administration of a Cell-Permeable Caveolin-1 Peptide Prevents the Development of Monocrotaline-Induced Pulmonary Hypertension and Right Ventricular Hypertrophy

Cited by 94 publications

References 36 publications

Cytoplasmic provenance of STAT3 and PY-STAT3 in the endolysosomal compartments in pulmonary arterial endothelial and smooth muscle cells: implications in pulmonary arterial hypertension

Cytoplasmic provenance of STAT3 and PY-STAT3 in the endolysosomal compartments in pulmonary arterial endothelial and smooth muscle cells: implications in pulmonary arterial hypertension

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

Decreased expression of caveolin 1 in patients with systemic sclerosis: Crucial role in the pathogenesis of tissue fibrosis

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