Increased Rho-kinase expression and activity and pulmonary endothelial dysfunction in smokers with normal lung function

Duong‐Quy, Sy; Dao, Pierre; Hua-Huy, T.; Guilluy, Christophe; Pacaud, Pierre; Dinh-Xuan, Anh Tuan

doi:10.1183/09031936.00056610

Cited by 29 publications

(30 citation statements)

References 29 publications

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“…It is known that smokers and COPD patients display increased levels of expression of RhoA-GTP as well the downstream factor Rho-kinase, which is involved in endothelial dysfunction, vascular contractility and remodelling [33]. As we previously found in HPAECs [13], the ability of CSE to upregulate RhoA-GTP activity was preventable by bosentan, BQ123 and, to a lesser extent, BQ788 treatment.…”

Section: Discussionmentioning

confidence: 51%

Bosentan inhibits cigarette smoke-induced endothelin receptor expression in pulmonary arteries

Milara

Gabarda²,

Juan³

et al. 2011

Eur Respir J

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The endothelin (ET) system contributes to lung vascular tension and remodelling in smokers and chronic obstructive pulmonary disease (COPD) patients.This study examined the effect of cigarette smoke (CS) on ET receptor A (ETA) and B (ETB) expression in human pulmonary artery smooth muscle cells (HPASMCs) and human small intrapulmonary arteries, as well as their functional consequences.CS extract (CSE) increased ETA and ETB expression in HPASMCs and small intrapulmonary arteries, which was attenuated by bosentan, the ETA antagonist BQ123 and the ETB antagonist BQ788, and by blocking ET-1 with a monoclonal antibody against ET-1, suggesting a feed-forward mechanism mediated by ET-1 release. ET receptor (ETR) antagonism attenuated the CSE-induced HPASMC proliferation. Furthermore, CSE exposure increased the acute ET-1-induced small intrapulmonary artery contraction, which was attenuated by bosentan, BQ123 and BQ788. Pulmonary arteries from smokers and COPD patients showed a higher expression of ETA and ETB than those of nonsmoker patients.These results show a novel mechanism by which ETR blockade attenuates CS-induced ETR overexpression and, subsequently, small intrapulmonary artery tension. These data may be of potential value to explain therapeutic effects of bosentan in some forms of disproportionate pulmonary hypertension in COPD patients.KEYWORDS: Bosentan, cigarette smoke, endothelin receptor, human pulmonary artery smooth muscle cells, precision-cut lung slice P ulmonary hypertension (PH) is a relatively common form of cigarette smoke (CS)-induced lung disease. PH develops in ,6% of subjects with chronic obstructive pulmonary disease (COPD) but is present in ,40% of patients with a forced expiratory volume in 1 s of ,1 L [1, 2]. The pathogenesis of PH in COPD is unclear. Current studies suggest that PH is caused by the direct effects of CS on the intrapulmonary vessels by the secretion of a number of vasoconstrictive/proliferative peptides, such as endothelin (ET) or vascular endothelial growth factor, which subsequently contribute to vascular remodelling and the development of PH [3]. The circulating levels of ET-1 are elevated after exposure to CS in humans [4] and it has been shown that ET-1 correlates with pulmonary systolic pressure in COPD patients with PH [5], suggesting that ET-1 is involved in CS-induced vascular remodelling. ET-1 activates two receptors, ETA and ETB, which are located in pulmonary artery smooth muscle cells (PASMCs), whilst exclusively ETB are present in endothelial cells. Both ETA and ETB mediate proliferation and contractility in PASMCs from small pulmonary arteries, while endothelial ETB mediates vasodilation in normal pulmonary arteries. ETB upregulation has been observed in human blood vessels from patients with ischaemic heart disease [6], hypertension [7] and severe PH [8]. More recently, it has been shown that CS extract (CSE) induces ETA and ETB overexpression in resistant cerebral arteries from rats by a mechanism implicating the activation of the intracellular m...

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Section: Discussionmentioning

confidence: 51%

Bosentan inhibits cigarette smoke-induced endothelin receptor expression in pulmonary arteries

Milara

Gabarda²,

Juan³

et al. 2011

Eur Respir J

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“…Pulmonary endothelial dysfunction, based on pulmonary arterial relaxation response and vasodilatory eNOS expression, is present in smokers with normal lung function (Duong-Quy, et al, 2011). The mechanism may occur via ROCK inhibition of NO synthesis.…”

Section: Pulmonary Diseasementioning

confidence: 99%

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

Yeganeh

Wiechec

Ande

et al. 2014

Pharmacology & Therapeutics

136

129

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The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA. Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate. The blockbuster statin drugs (‘statins’) directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering. In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD), and cancer.

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“…Simvastatin might inhibit the hypoxiainduced vasoconstriction mediated by RhoA/Rho-kinase [32]. Recent study realized by our group showed the activity of RhoA/Rho-kinase signaling pathway had been increased in smokers and in smokers with COPD [30]. It suggests that statin might be a potential additional treatment in severe COPD with hypoxia at rest.…”

Section: Discussionmentioning

confidence: 94%

“…In patients with severe COPD, LTOT prevents not only the progression to right heart failure but also the survival free of acute exacerbation [29]. Moreover, in patients with cigarette smokinginduced COPD having hypoxia at rest, even though in acting smoking with normal lung function, LTOT might prevent hypoxia-related endothelial dysfunction and pulmonary vasoconstriction with the evolution toward pulmonary vascular remodelling and PAP [30,31].…”

Section: Discussionmentioning

confidence: 99%

Comparison of Long Term Oxygen-Therapy (LTOT) and LTOT Combined with Sildenafil and Simvastatin in the Treatment of Severe Chronic Obstructive Pulmonary (COPD) with Hypoxia at Rest and Severe Pulmonary Arterial Hypertension

Tran-Van¹,

Vo-Thi-Kim²,

Tran-Ngoc³

et al. 2017

Vasc Med Surg

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Increased Rho-kinase expression and activity and pulmonary endothelial dysfunction in smokers with normal lung function

Cited by 29 publications

References 29 publications

Bosentan inhibits cigarette smoke-induced endothelin receptor expression in pulmonary arteries

Bosentan inhibits cigarette smoke-induced endothelin receptor expression in pulmonary arteries

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

Comparison of Long Term Oxygen-Therapy (LTOT) and LTOT Combined with Sildenafil and Simvastatin in the Treatment of Severe Chronic Obstructive Pulmonary (COPD) with Hypoxia at Rest and Severe Pulmonary Arterial Hypertension

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