Monocrotaline-induced pulmonary arterial hypertension: Time-course of injury and comparative evaluation of macitentan and Y-27632, a Rho kinase inhibitor

Novelli, Deborah; Fumagalli, Francesca; Staszewsky, Lidia; Ristagno, Giuseppe; Olivari, Davide; Masson, Serge; Giorgio, Daria De; Ceriani, Sabina; Affatato, Roberta; Logu, Francesco De; Nassini, Romina; Milioli, Marco; Facchinetti, Fabrizio; Cantoni, Silvia; Trevisani, Marcello; Letizia, Teresa; Russo, Ilaria; Salio, Monica; Latini, Roberto

doi:10.1016/j.ejphar.2019.172777

Cited by 13 publications

(13 citation statements)

References 33 publications

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“…Strong evidence from cell studies indicates that ROCK is activated [ 19 ] and contributes to PH pathogenesis and its modulation could interfere with the alterations induced in different PH experimental models, using monocrotaline (MCT) [ 49 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 ] or hypoxia [ 35 , 126 , 162 , 198 , 202 , 204 , 205 , 206 ].…”

Section: Rock In Preclinical Models Of Phmentioning

confidence: 99%

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ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

Montagnoli

Sudo

et al. 2021

Cells

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Pulmonary hypertension (PH) is a cardiovascular disease caused by extensive vascular remodeling in the lungs, which ultimately leads to death in consequence of right ventricle (RV) failure. While current drugs for PH therapy address the sustained vasoconstriction, no agent effectively targets vascular cell proliferation and tissue inflammation. Rho-associated protein kinases (ROCKs) emerged in the last few decades as promising targets for PH therapy, since ROCK inhibitors demonstrated significant anti-remodeling and anti-inflammatory effects. In this review, current aspects of ROCK inhibition therapy are discussed in relation to the treatment of PH and RV dysfunction, from cell biology to preclinical and clinical studies.

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Section: Rock In Preclinical Models Of Phmentioning

confidence: 99%

“…In addition to fasudil, several substances described as ROCK inhibitors have been investigated ( Table 1 ) [ 49 , 195 , 196 , 197 , 198 , 199 , 201 ]. Recently, fasudil dichloroacetate (FDCA) was synthesized and demonstrated a preserved inhibitory profile of ROCK2 [ 201 ].…”

Section: Rock In Preclinical Models Of Phmentioning

confidence: 99%

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

Montagnoli

Sudo

et al. 2021

Cells

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“…It has been demonstrated that ET-1 induces pulmonary vasoconstriction through activation of RhoA, which is a small GTP protein [7]. Many studies have reported that the RhoA/Rho-kinase pathways implicate pulmonary hypertension [8,9,10]. Additionally, endothelin receptors are G-protein-coupled receptors [7], and we have previously demonstrated that Gi, which is a heterotrimeric G protein, functions upstream of RhoA activation [11].…”

Section: Introductionmentioning

confidence: 79%

Endothelin-1 upregulates activin receptor-like kinase-1 expression via Gi/RhoA/Sp-1/Rho kinase pathways at transcriptional and post-transcriptional levels in human pulmonary arterial endothelial cells

Sugimoto

Yokokawa

Misaka

et al. 2020

Preprint

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BackgroundsPulmonary arterial hypertension (PAH) is a disease with poor prognosis that is characterized by pulmonary vasoconstriction and organic stenosis due to abnormal proliferation of pulmonary vascular cells. It has been demonstrated that endothelin (ET)-1 induces pulmonary vasoconstriction through activation of RhoA. Moreover, we previously demonstrated that Gi, a heterotrimeric G protein, functions upstream of RhoA activation. A gene mutation of activin receptor-like kinase (ACVRL)-1 is recognized in idiopathic or heritable PAH patients. However, little is known about the association between ET-1 and ACVRL-1. In the present study, we investigated the effect of ET-1 on ACVRL-1 expression and aimed to delineate the involvement of the Gi/RhoA/Rho kinase pathway.MethodsET-1 was added to culture medium of human pulmonary arterial endothelial cells (PAECs), and ACVRL-1 expression levels were analyzed using western blotting and quantitative polymerase chain reaction. The promoter activity of ACVRL-1 was evaluated by dual luciferase assay. Before adding ET-1 to the PAECs, pretreatment with pertussis toxin (PTX) or exoenzyme C3 transferase (C3T) was performed for the inhibition of Gi or RhoA, respectively. Rho kinase was inhibited by Y27632. Active form of RhoA (GTP-RhoA) was assessed by pull-down assay.ResultsACVRL-1 expression was increased by ET-1 in the PAECs. Pull-down assay revealed that ET-1 rapidly induced a GTP-loading of RhoA. The ET-1-induced RhoA activation was suppressed by pretreatment with PTX or C3T. Further, PTX, C3T, and Y27632 suppressed the ET-1-induced ACVRL-1 expression. The activity of ACVRL-1 promotor and the lifespan of ACVRL-1 mRNA was increased by ET-1. Sp-1, which is one of the transcriptional factors of ACVRL-1, peaked 15 min after adding ET-1 to the PAECs. PTX and C3T prevented the increase of Sp-1 induced by ET-1.ConclusionThe present study demonstrated that ET-1 increases ACVRL-1 expression at the transcriptional and post-transcriptional levels in human PAECs via the Gi/RhoA/Rho kinase pathway with involvement of Sp-1.

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“…PAH was induced in 11 male Wistar rats (6–8 weeks, Charles River, Calco, Italy) weighting 306 ± 6 g by subcutaneous injection of 60 mg/kg monocrotaline (Sigma-Aldrich, Inc., St. Louis, MO, USA), as previously described. 3 …”

mentioning

confidence: 99%

“…After 24-hour treatment, echocardiography was performed (Arietta V70, Hitachi-Aloka, Milano, Italy) inside the chamber with the animals anesthetized. As previously described, 3 pulsed-wave Doppler of pulmonary outflow was recorded in parasternal short-axis view at the level of the great vessels and pulmonary artery acceleration time was measured as the time of systolic flow to peak pulmonary outflow velocity. The RV stroke volume (RVSV) and cardiac output (RVCO) were calculated by the formulas: RVSV = π × (RV outflow tract/2) 2 × RV outflow tract velocity time, RVCO = SV × heart rate.…”

mentioning

confidence: 99%