Involvement of RhoA/Rho kinase signaling in protection against monocrotaline-induced pulmonary hypertension in pneumonectomized rats by dehydroepiandrosterone

Homma, Noriyuki; Nagaoka, Tetsutaro; Karoor, Vijaya; Imamura, Masatoshi; Taraseviciene‐Stewart, Laimute; Walker, Lori A.; Fagan, Karen A.; McMurtry, Ivan F.; Oka, Masahiko

doi:10.1152/ajplung.90251.2008

Cited by 79 publications

(65 citation statements)

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“…Owing to its role in key cell functions, hyperactive ROCK signalling results in cardiovascular disorders associated with sustained abnormal vasoconstriction and promotion of vascular remodelling [8,9]. Studies on animal models of pulmonary hypertension (PH), such as chronic hypoxia-, monocrotaline (MCT)-, vascular endothelial growth factor receptor inhibition and chronic hypoxia-, pneumonectomy and MCT-and bleomycin-induced PH suggest that increased ROCK is involved in the pathogenesis [10][11][12][13][14][15][16]. Moreover, data are emerging that implicate ROCK signalling in clinical PH and that ROCK inhibition provides beneficial acute effects in patients [17][18][19][20][21][22][23].…”

mentioning

confidence: 99%

Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension

Dahal¹,

Kosanovic²,

Pk³

et al. 2010

European Respiratory Journal

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An accumulating body of evidence incriminates Rho kinase (ROCK) in the pathogenesis of pulmonary hypertension (PH). The therapeutic efficacy of azaindole-1, a novel highly selective and orally active ROCK inhibitor, has not yet been investigated in PH.This study aimed to investigate the effects of azaindole-1 on 1) acute hypoxic pulmonary vasoconstriction (HPV), 2) proliferation of pulmonary arterial smooth muscle cells (PASMCs) and 3) animal models of PH.Azaindole-1 significantly inhibited HPV in isolated, ventilated and buffer-perfused murine lungs and proliferation of primary rat PASMCs in vitro. Azaindole-1 was administered orally from 21 to 35 days after monocrotaline (MCT) injection in rats and hypoxic exposure in mice. Azaindole-1 (10 and 30 mg per kg body weight per day in rats and mice, respectively) significantly improved haemodynamics and right ventricular hypertrophy. Moreover, the medial wall thickness and muscularisation of peripheral pulmonary arteries were ameliorated. Azaindole-1 treatment resulted in a decreased immunoreactivity for phospho-myosin phosphatase target subunit 1 and proliferating cell nuclear antigen in pulmonary vessels of MCT-injected rats, suggesting an impaired ROCK activity and reduced proliferating cells.Azaindole-1 provided therapeutic benefit in experimental PH, and this may be attributable to its potent vasorelaxant and antiproliferative effects. Azaindole-1 may offer a useful approach for treatment of PH.KEYWORDS: Azaindole-1, hypoxia, monocrotaline, pulmonary hypertension, Rho kinase P ulmonary arterial hypertension (PAH) is a chronic fatal disease characterised by sustained elevation of pulmonary artery pressure and reduced exercise tolerance. As a consequence, the right ventricular afterload increases and culminates in right ventricular failure. PAH has a complex pulmonary vascular pathophysiology, including vasoconstriction, vascular remodelling and in situ thrombosis. The progressive vascular remodelling, the hallmark of PAH pathology, is attributable to abnormalities in vascular cells, such as increased proliferation and resistance to apoptosis [1][2][3]. However, the precise molecular mechanism is incompletely understood, and so a therapeutic approach for curing this disease is currently sought after.The small GTPase RhoA is one of the members of the Rho protein family that regulate cellular functions such as contraction, motility, proliferation and apoptosis, and Rho kinases (ROCKs) are the best characterised downstream targets for RhoA [4]. Two isoforms of the serine/threonine kinase ROCK have been identified: . ROCKs are ubiquitously expressed in tissues including vasculature and heart. Owing to its role in key cell functions, hyperactive ROCK signalling results in cardiovascular disorders associated with sustained abnormal vasoconstriction and promotion of vascular remodelling [8,9]. Studies on animal models of pulmonary hypertension (PH), such as chronic hypoxia-, monocrotaline (MCT)-, vascular endothelial growth factor receptor inhibition and chron...

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mentioning

confidence: 99%

Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension

Dahal¹,

Kosanovic²,

Pk³

et al. 2010

European Respiratory Journal

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“…The beneficial effect of DHEA in PH has also been observed in the monocrotaline-induced PH rat model, which is closer to the pathophysiology of idiopathic PH (11), although further studies investigating its effect on plexiform lesions remain to be performed. With respect to the mechanism of action, in addition to the modulation of Ca 2+ -activated potassium channel expression and activity, other cellular mechanisms have already been demonstrated and include a protective effect on the vascular endothelium (32), an activation of the RhoA/Rho kinase signaling pathway (11), a decrease in vascular remodeling with activation of apoptosis, and a decrease in cellular proliferation via the inhibition of transcription factors such as hypoxia inducible factor-1 or nuclear factor of activated T cell (27,33).…”

Section: Dhea Prevents Pulmonary Hypertensionmentioning

confidence: 78%

“…Articles been shown to inhibit RhoA/ROCK pathway and to decrease hypoxia inducible factor-1a in PASMCs (11,27). PA hyperreactivity is an additional key feature in PH.…”

Section: Dhea Prevents Pulmonary Hypertensionmentioning

confidence: 99%

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Beneficial effect of dehydroepiandrosterone on pulmonary hypertension in a rodent model of pulmonary hypertension in infants

et al. 2013

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Background: Pulmonary hypertension (PH) is a disease that affects the adult or infant population. Dehydroepiandrosterone (DHEA), a steroid hormone, has been previously shown to prevent and to reverse PH in an adult rat model. We thus investigated its effect in a rat-pup model of chronic hypoxic PH. Methods: Animals were maintained for 3 wk in a hypobaric chamber to induce PH, with or without concomitant treatment with DHEA (30 mg/kg every alternate day). results: DHEA significantly reduced mean pulmonary artery pressure (measured by right cardiac catheterization), pulmonary artery remodeling (evaluated by histology), and rightventricular hypertrophy (measured by echography and by the Fulton index). At the level of the pulmonary artery smooth muscle cell (PASMC), DHEA increased activity and expression of the large-conductance Ca2+-activated potassium channel (BK Ca ) (assessed by means of the patch clamp technique). DHEA also inhibited both serotonin-and KCl-induced contraction and smooth muscle cell proliferation. conclusion: Collectively, these results indicate that DHEA prevents PH in infant rats and may therefore be clinically relevant for the management of PH in human infants. P ulmonary hypertension (PH) is a disease that affects both adults and infants. PH is characterized by increased pulmonary vascular pressure and resistance, which can lead, in rare cases in infants, to right-ventricular failure and ultimately to death (1). Increased reactivity to agonists and remodeling of small pulmonary arteries (PAs) are landmarks of PH (2,3). In infants, there are a variety of PH phenotypes, some of which are specific to this age group: (i) PH secondary to congenital heart disease with a left-right shunt, (ii) persistent PH of the newborn due to the absence of a drop in neonatal pulmonary resistance, (iii) acute or chronic pulmonary disease induced by hypoxemia, and (iv) idiopathic forms (4,5). Pharmacological treatments that mainly aim at vasodilating PAs, e.g., prostanoid analog, endothelin receptor antagonists, or phosphodiesterase inhibitors (2,6), still need to be comprehensively evaluated in pediatric patients. It is thus essential to develop new treatments to prevent and/or reverse PH in this population.Dehydroepiandrosterone (DHEA) is the most abundant adrenal steroid, and serum concentration of its sulfate ester is approximately 20-fold higher than that of any other circulating steroid hormone (7,8). In different models of adult rats with PH, we (9) and others (10,11) have shown that DHEA prevents and reverses PH and the resulting right-ventricular (RV) hypertrophy as well as small PA remodeling. However, similar studies have not been performed in newborn or infant animals. We have thus investigated the effect of DHEA in a model of infant rats in which PH was induced. We have observed that chronic treatment with DHEA (30 mg/kg every alternate day) is able to prevent PH and its associated cardiovascular alterations such as RV hypertrophy, pulmonary vascular hyperreactivity, and smooth muscle cell proliferat...

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“…Finally, activation of the RhoA/ROCK signaling pathway contributes to vasoconstriction in VSMCs, a pathway that plays an important role in the pathogenesis of PAH. Chronic DHEA treatments in PAH rat model were described to decrease RhoA/ROCK signaling pathway activity by multiple mechanisms, including preservation of sGC expression and inhibition of ROCK cleavage [70].…”

Section: Dhea Vasodilating Propertiesmentioning

confidence: 99%

Dehydroepiandrosterone, Over-studied but Under-used in the Treatment of Vascular Remodeling Diseases

Paulin¹

2013

J Steroids Horm Sci

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Involvement of RhoA/Rho kinase signaling in protection against monocrotaline-induced pulmonary hypertension in pneumonectomized rats by dehydroepiandrosterone

Cited by 79 publications

References 56 publications

Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension

Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension

Beneficial effect of dehydroepiandrosterone on pulmonary hypertension in a rodent model of pulmonary hypertension in infants

Dehydroepiandrosterone, Over-studied but Under-used in the Treatment of Vascular Remodeling Diseases

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