A Critical Role for p130<sup>Cas</sup> in the Progression of Pulmonary Hypertension in Humans and Rodents

Tu, Ly; Man, Frances S. de; Girerd, Barbara; Huertas, Alice; Chaumais, Marie-Camille; Lecerf, Florence; François, Charlène; Perros, Frédèric; Dorfmüller, Peter; Fadel, Élie; Montani, David; Eddahibi, Saadia; Humbert, Marc; Guignabert, Christophe

doi:10.1164/rccm.201202-0309oc

Cited by 82 publications

(100 citation statements)

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“…Indeed, accumulating evidence supports the concept that increased endothelial apoptosis at the early stage and decreased endothelial apoptosis at later stages of the disease could contribute to PAH [18]. Consistent with this hypothesis, we have recently reported that primary pulmonary endothelial cells generated from PAH lung specimens exhibit various intrinsic abnormalities and present a modified pro-proliferative, apoptotic-resistant phenotype [4,17,19]. Although we have shown that increased activity of the FGF2 autocrine loop is among the mechanisms needed to acquire this altered endothelial phenotype in PAH [17], the exact nature of pulmonary endothelial cell modification during PAH and the balance between apoptotic and anti-apoptotic phenotypes remain only partially understood.…”

Section: Circulating Microparticles As Regulators Of Endothelial Dysfsupporting

confidence: 69%

Cellular microparticles in the pathogenesis of pulmonary hypertension

et al. 2012

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Pulmonary hypertension (PH) is a fatal disease with no treatment options, characterised by elevated pulmonary vascular resistanzce and secondary right ventricular failure. The aetiology of pulmonary arterial hypertension is multiple and its pathogenesis is complex. Although the exact role of cellular microparticles remains partially understood, there is increasing evidence to suggest an active role for microparticles in PH pathophysiology. Patients with PH exhibited higher circulating levels of microparticles compared to control subjects and in vitro or in vivo generated microparticles can induce endothelial dysfunction, interfere with coagulation pathways or modulate inflammatory phenomenon. Whether or not these new conveyors of biological information contribute to the acquisition and/or maintenance of the altered endothelial phenotype is unexplored in PH and requires further study. @ERSpublications Patients with PH have elevated circulating levels of microparticles which may contribute to disease pathophysiology

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Section: Circulating Microparticles As Regulators Of Endothelial Dysfsupporting

confidence: 69%

Cellular microparticles in the pathogenesis of pulmonary hypertension

et al. 2012

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“…Isolation, culture and treatment of human pulmonary endothelial cells, PA-SMCs and peripheral blood mononuclear cells Human pulmonary endothelial cells (P-ECs) and PA-SMCs were isolated from distal pulmonary arteries and cultured as previously described [12][13][14]. Cells (early passages ⩽5) were placed in serum-free medium for 24 h and exposed with dimethyloxaloylglycine (DMOG, 0.25 mM) (Enzo Life Sciences, Villeurbanne, France), dichloroacetate (DCA, 5 mM) (Sigma-Aldrich, Lyon, France), and recombinant Ob (10 and 100 ng·mL ) and ten times more (100 ng·mL −1 ) were used, based on the literature [15][16][17].…”

Section: Subjectsmentioning

confidence: 99%

“…Cells (early passages ⩽5) were placed in serum-free medium for 24 h and exposed with dimethyloxaloylglycine (DMOG, 0.25 mM) (Enzo Life Sciences, Villeurbanne, France), dichloroacetate (DCA, 5 mM) (Sigma-Aldrich, Lyon, France), and recombinant Ob (10 and 100 ng·mL ) and ten times more (100 ng·mL −1 ) were used, based on the literature [15][16][17]. Proliferation was assessed by 5-bromo-2-deoxyuridine (BrdU) incorporation [12].…”

Section: Subjectsmentioning

confidence: 99%

“…Animals were anesthetised with isoflurane and haemodynamic parameters were measured as previously described in mice (right ventricular systolic pressure (RVSP)) [20] and in rats (mean PAP and pulmonary vascular resistance (PVR)) [12]. Then, blood was removed for PBMC analyses and the thorax was opened and the left lung immediately removed and frozen.…”

Section: Animal Models and Haemodynamic Measurementsmentioning

confidence: 99%

“…The right was fixed in the distended state with formalin buffer. Right ventricular hypertrophy (RVH) Fulton index and the percentage of muscularised vessels were determined as previously described [12].…”

Section: Animal Models and Haemodynamic Measurementsmentioning

confidence: 99%

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Leptin signalling system as a target for pulmonary arterial hypertension therapy

Huertas

Thuillet

et al. 2015

Eur Respir J

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Excessive proliferation of pulmonary arterial smooth muscle cells (PA-SMCs) and perivascular inflammation lead to pulmonary arterial hypertension (PAH) progression, but they are not specifically targeted by the current therapies. Since leptin (Ob) and its main receptor ObR-b contribute to systemic vascular cell proliferation and inflammation, we questioned whether targeting Ob/ObR-b axis would be an effective antiproliferative and anti-inflammatory strategy against PAH.In idiopathic PAH (iPAH), using human lung tissues and primary cell cultures (early passages ⩽5), we demonstrate that pulmonary endothelial cells (P-ECs) over produce Ob and that PA-SMCs overexpress ObR-b. Furthermore, we obtain evidence that Ob enhances proliferation of human PA-SMCs in vitro and increases right ventricular systolic pressure in Ob-treated mice in the chronic hypoxia-induced pulmonary hypertension (PH) model. Using human cells, we also show that Ob leads to monocyte activation and increases cell adhesion molecule expression levels in P-ECs. We also find that Ob/ObR-b axis contributes to PH susceptibility by using ObR-deficient rats, which display less severe hypoxia-induced PH ( pulmonary haemodynamics, arterial muscularisation, PA-SMC proliferation and perivascular inflammation). Importantly, we demonstrate the efficacy of two curative strategies using a soluble Ob neutraliser and dichloroacetate in hypoxia-induced PH.We demonstrate here that Ob/ObR-b axis may represent anti-proliferative and anti-inflammatory targets in PAH. @ERSpublications Targeting Ob/ObR-b axis represents an important tool for anti-proliferative and antiinflammatory strategies in PH http://ow.ly/I00jh

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CAS proteins in health and disease: An update

et al. 2014

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The CAS family of scaffolding proteins has increasingly attracted scrutiny as important for regulation of cancer-associated signaling. BCAR1 (also known as p130Cas), NEDD9 (HEF1, Cas-L), EFS (Sin), and CASS4 (HEPL) are regulated by and mediate cell attachment, growth factor, and chemokine signaling. Altered expression and activity of CAS proteins is now known to promote metastasis and drug resistance in cancer, influence normal development, and contribute to the pathogenesis of heart and pulmonary disease. In this article, we provide an update on recently published studies describing signals regulating and regulated by CAS proteins, and evidence for biological activity of CAS proteins in normal development, cancer and other pathological conditions.

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A Critical Role for p130^Cas in the Progression of Pulmonary Hypertension in Humans and Rodents

Abstract: Our findings demonstrate that p130(Cas) signaling plays a critical role in experimental and idiopathic PAH by modulating pulmonary vascular cell migration and proliferation and by acting as an amplifier of RTK downstream signals.

Cited by 82 publications

References 48 publications

Cellular microparticles in the pathogenesis of pulmonary hypertension

Cellular microparticles in the pathogenesis of pulmonary hypertension

Leptin signalling system as a target for pulmonary arterial hypertension therapy

CAS proteins in health and disease: An update

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A Critical Role for p130Cas in the Progression of Pulmonary Hypertension in Humans and Rodents

Abstract: Our findings demonstrate that p130(Cas) signaling plays a critical role in experimental and idiopathic PAH by modulating pulmonary vascular cell migration and proliferation and by acting as an amplifier of RTK downstream signals.

Cited by 82 publications

References 48 publications

Cellular microparticles in the pathogenesis of pulmonary hypertension

Cellular microparticles in the pathogenesis of pulmonary hypertension

Leptin signalling system as a target for pulmonary arterial hypertension therapy

CAS proteins in health and disease: An update

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Product

Resources

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A Critical Role for p130^Cas in the Progression of Pulmonary Hypertension in Humans and Rodents