Prednisolone Inhibits Proliferation of Cultured Pulmonary Artery Smooth Muscle Cells of Patients With Idiopathic Pulmonary Arterial Hypertension

Ogawa, Aiko; Nakamura, Kazufumi; Matsubara, Hiromi; Fujio, Hideki; Ikeda, Tetsuya; Kobayashi, Kaoru; Miyazaki, Ikuko; Asanuma, Masato; Miyaji, Kagami; Miura, Daiji; Kusano, Kengo; Date, Hiroshi; Ohe, Tohru

doi:10.1161/circulationaha.105.536169

Cited by 56 publications

(65 citation statements)

References 29 publications

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“…The antiproliferative findings in this study are consistent with a study of prednisolone on platelet-derived growth factor-stimulated PASMCs from PAH patients [47], although that study used much higher doses (equating to 3610 -5 and 3610 -4 M dexamethasone).…”

Section: Discussionsupporting

confidence: 89%

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

Lc¹,

Montani²,

Tchérakian³

et al. 2010

Eur Respir J

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Pulmonary arterial hypertension (PAH) is associated with dysregulated bone morphogenetic protein receptor (BMPR)-II signaling and pulmonary vascular inflammation. We evaluated the effects of dexamethasone on monocrotaline (MCT)-induced PAH in rats for potential reversal of PAH at late time-points.Saline-treated control, MCT-exposed, MCT-exposed and dexamethasone-treated rats (5 mg?kg ) were evaluated at day 28 and day 35 following MCT for haemodynamic parameters, right ventricular hypertrophy, morphometry, immunohistochemistry, and IL6 and BMPR2 expression.Dexamethasone improved haemodynamics and pulmonary vascular remodelling, preventing PAH development at early (day 1-14 and 1-28) and reversing PAH at late (day 14-28 and 21-35) time-points following MCT, as well as improving survival in MCT-exposed rats compared with controls. Both MCT-induced pulmonary IL6 overexpression and interleukin (IL)-6-expressing adventitial inflammatory cell infiltration were reduced with dexamethasone. This was associated with pulmonary BMPR2 downregulation following MCT, which was increased with dexamethasone, in whole lung and control pulmonary artery smooth muscle cells. Dexamethasone also reduced proliferation of rat pulmonary artery smooth muscle cells in vitro.Experimental PAH can be prevented and reversed by dexamethasone, and survival is improved. In this model, mechanisms may involve reduction of IL-6-expressing inflammatory cells, restoration of pulmonary BMPR2 expression and reduced proliferation of vascular smooth muscle cells.

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Section: Discussionsupporting

confidence: 89%

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

Lc¹,

Montani²,

Tchérakian³

et al. 2010

Eur Respir J

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“…When a vasoconstrictive or mitogenic ligand binds with its receptor in the plasma membrane in PASMC, a rise in [Ca 2ϩ ] cyt due to Ca 2ϩ release and/or entry is an important signaling mechanism for agonist-mediated PASMC contraction and mitogen-mediated PASMC proliferation. Compared with PASMC from normal subjects, many studies have demonstrated that 1) the proliferation rate (determined by cell number, DNA content, and 3 H-thymidine incorporation) is significantly accelerated (37,38,59) and 2) the store depletion-mediated Ca 2ϩ entry is enhanced in PASMC from IPAH patients (59), as well as in PASMC from chronically hypoxic animals (32,57). Therefore, PASMC from IPAH patients may undergo phenotypic changes that make the cells more prone (inclined) to proliferation and contraction or to activation by contractile agonists and mitogenic factors.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Na⁺/Ca²⁺ exchanger contributes to the enhanced Ca²⁺ entry in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension

Zhang

Dong

Rubin

et al. 2007

American Journal of Physiology-Cell Physiology

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] cyt ) in pulmonary artery smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction (49) and an important stimulus for pulmonary vascular medial hypertrophy by stimulating PASMC proliferation (7,22). Removal of extracellular Ca 2ϩ or blockade of Ca 2ϩ influx significantly inhibits agonist-mediated pulmonary vasoconstriction (35) and markedly attenuates mitogen-mediated PASMC proliferation (24,52,60). These observations indicate that Ca 2ϩ entry through Ca 2ϩ channels and/or Ca 2ϩ transporters in the plasma membrane is one of the necessary prerequisites for the control of pulmonary vascular contractility and PASMC proliferation and growth.

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“…Ogawa and coworkers reported an immunosuppressant, prednisolone, to have an antiproliferative effect on cultured SMC of pulmonary arteries from patients with idiopathic PAH, thus suggesting that prednisolone may be potentially useful therapeutically in patients with idiopathic PAH (82). Moreover, they have shown that PDGF-induced nuclear translocation of NF-kB may play an important role in stimulating pulmonary arterial SMC proliferation (and/or enhancing pulmonary arterial SMC survival), whereas prednisolone may exert both anti-inflammatory and antiproliferative effects on PASMC by inhibiting NF-kB nuclear translocation (83).…”

Section: The Role Of Immunitymentioning

confidence: 99%

Reversible or Irreversible Remodeling in Pulmonary Arterial Hypertension

Sakao¹,

Tatsumi²,

Voelkel³

2010

Am J Respir Cell Mol Biol

151

120

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Vascular remodeling is an important pathological feature of pulmonary arterial hypertension (PAH), which leads to increased pulmonary vascular resistance, with marked proliferation of pulmonary artery smooth muscle cells (SMC) and/or endothelial cells (EC). Successful treatment of experimental PAH with a platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitor offers the perspective of ''reverse remodeling'' (i.e., the regression of established pulmonary vascular lesions). Here we ask the question: which forms of pulmonary vascular remodeling are reversible and can such remodeling caused by angiogenic proliferation of EC be reversed? It is important to emphasize that the report showing reduction of vascular remodeling by PDGF receptor tyrosine kinase inhibitor showed only a reduction of the pulmonary artery muscularization in chronic hypoxia and monocrotaline models, which lack the feature of clustered proliferated EC in the lumen of pulmonary arteries. The regression of vascular muscularization is an important manifestation, whereby proliferative adult SMC convert back to a nonproliferative state. In contrast, in vitro experiments assessing the contribution of EC to the development of PAH demonstrated that phenotypically altered EC generated as a consequence of a vascular endothelial growth factor receptor blockade did not reverse to normal EC. Whereas it is suggested that the proliferative state of SMC may be reversible, it remains unknown whether phenotypically altered EC can switch back to a normal monolayer-forming EC. This article reviews the pathogenetic concepts of severe PAH and explains the many forms in PAH with reversible or irreversible remodeling.Keywords: remodeling; PAH; endothelial cell; smooth muscle cell Pulmonary vascular remodeling is an important pathological feature of pulmonary arterial hypertension (PAH), which leads to increased pulmonary vascular resistance and reduced compliance, with marked proliferation of pulmonary artery smooth muscle cells (SMC) and/or endothelial cells (EC) resulting in the obstruction of blood flow in the resistance pulmonary arteries (1, 2). In a recent Perspective article, Rai and coworkers (3) characterized severe PAH as a quasi-neoplastic, angioproliferative disorder, and this concept provides a new framework for antiproliferative, antiangiogenic therapy in severe PAH.Successful treatment with a platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitor of experimental pulmonary hypertension offers the prospect of ''reverse remodeling'' (i.e., the regression of established pulmonary vascular lesions) (4).This review asks the question: which forms of pulmonary vascular remodeling are reversible and can the remodeling caused by the angiogenic proliferation of EC be reversed (5-8)? It is important to emphasize that the report showing a reduction of vascular remodeling by PDGF receptor tyrosine kinase inhibitor (4) showed only the reduction of pulmonary artery muscularization in chronic hypoxia and monocrotaline models, which lack ...

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Prednisolone Inhibits Proliferation of Cultured Pulmonary Artery Smooth Muscle Cells of Patients With Idiopathic Pulmonary Arterial Hypertension

Cited by 56 publications

References 29 publications

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

Upregulation of Na⁺/Ca²⁺ exchanger contributes to the enhanced Ca²⁺ entry in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension

Reversible or Irreversible Remodeling in Pulmonary Arterial Hypertension

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Prednisolone Inhibits Proliferation of Cultured Pulmonary Artery Smooth Muscle Cells of Patients With Idiopathic Pulmonary Arterial Hypertension

Cited by 56 publications

References 29 publications

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

Upregulation of Na+/Ca2+ exchanger contributes to the enhanced Ca2+ entry in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension

Reversible or Irreversible Remodeling in Pulmonary Arterial Hypertension

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Upregulation of Na⁺/Ca²⁺ exchanger contributes to the enhanced Ca²⁺ entry in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension