Novel ROCK inhibitors for the treatment of pulmonary arterial hypertension

Shaw, Duncan; Hollingworth, Greg; Soldermann, Nicolas; Sprague, Elizabeth R.; Schüler, W.; Vangrevelinghe, Eric; Duggan, Nicholas; Thomas, Matthew; Kosaka, Takatoshi; Waters, Nigel J.; Eis, Maurice J. van

doi:10.1016/j.bmcl.2014.09.002

Cited by 32 publications

(21 citation statements)

References 17 publications

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“…18 Two human isoforms, ROCK1 and ROCK2, have been shown to play distinct roles in cytoskeletal regulation. 19–23 ROCKs have been investigated in a variety of diseases, 24 and ROCK inhibition, using synthetic inhibitors, is being examined as a treatment option for pulmonary hypertension, 25 cancer, 26 glaucoma, 27 and certain neurological diseases. 28,29 In the retina, intravitreal injections of Y-27632, a synthetic pan ROCK inhibitor, were shown to protect photoreceptors from apoptosis and support retinal structure and function in the Royal College of Surgeons rat, a model of retinal dystrophy; however, RPE cells were not examined.…”

Section: Introductionmentioning

confidence: 99%

ROCK Inhibition Promotes Attachment, Proliferation, and Wound Closure in Human Embryonic Stem Cell–Derived Retinal Pigmented Epithelium

Croze

Thi

Clegg

2016

Trans. Vis. Sci. Tech.

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PurposeNonexudative (dry) age-related macular degeneration (AMD), a leading cause of blindness in the elderly, is associated with the loss of retinal pigmented epithelium (RPE) cells and the development of geographic atrophy, which are areas devoid of RPE cells and photoreceptors. One possible treatment option would be to stimulate RPE attachment and proliferation to replace dying/dysfunctional RPE and bring about wound repair. Clinical trials are underway testing injections of RPE cells derived from pluripotent stem cells to determine their safety and efficacy in treating AMD. However, the factors regulating RPE responses to AMD-associated lesions are not well understood. Here, we use cell culture to investigate the role of RhoA coiled coil kinases (ROCKs) in human embryonic stem cell–derived RPE (hESC-RPE) attachment, proliferation, and wound closure.MethodsH9 hESC were spontaneously differentiated into RPE cells. hESC-RPE cells were treated with a pan ROCK1/2 or a ROCK2 only inhibitor; attachment, and proliferation and cell size within an in vitro scratch assay were examined.ResultsPharmacological inhibition of ROCKs promoted hESC-RPE attachment and proliferation, and increased the rate of closure of in vitro wounds. ROCK inhibition decreased phosphorylation of cofilin and myosin light chain, suggesting that regulation of the cytoskeleton underlies the mechanism of action of ROCK inhibition.ConclusionsROCK inhibition promotes attachment, proliferation, and wound closure in H9 hESC-RPE cells. ROCK isoforms may have different roles in wound healing.Translational RelevanceModulation of the ROCK-cytoskeletal axis has potential in stimulating wound repair in transplanted RPE cells and attachment in cellular therapies.

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Section: Introductionmentioning

confidence: 99%

ROCK Inhibition Promotes Attachment, Proliferation, and Wound Closure in Human Embryonic Stem Cell–Derived Retinal Pigmented Epithelium

Croze

Thi

Clegg

2016

Trans. Vis. Sci. Tech.

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“…12 RhoA/ROCK axis was demonstrated to be involved in the PAH pathogenesis through modulating vasoconstriction and vascular remodelling, the main pathogenic events of PAH. 34 Moreover, Yu and the colleagues reported that in heparin-treated PASMCs, GEF, RhoA and ROCK were increased, leading to the down-regulated of p27, which contributed to the PASMC proliferation. 35 In the present research, we also found that RhoA was activated in PAH models and we firstly found RhoA could be activated by WIPF1.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies demonstrated that the activity of RhoA and Rho kinase was twofold in PAH patients compared to the healthy subjects 12 . RhoA/ROCK axis was demonstrated to be involved in the PAH pathogenesis through modulating vasoconstriction and vascular remodelling, the main pathogenic events of PAH 34 . Moreover, Yu and the colleagues reported that in heparin‐treated PASMCs, GEF, RhoA and ROCK were increased, leading to the down‐regulated of p27, which contributed to the PASMC proliferation 35 .…”

Section: Discussionmentioning

confidence: 99%

LncRNA PAXIP1‐AS1 fosters the pathogenesis of pulmonary arterial hypertension via ETS1/WIPF1/RhoA axis

Rong

Liu

Song

et al. 2021

J Cellular Molecular Medi

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Pulmonary arterial hypertension (PAH) is a life‐threatening disease featured with elevated pulmonary vascular resistance and progressive pulmonary vascular remodelling. It has been demonstrated that lncRNA PAXIP1‐AS1 could influence the transcriptome in PAH. However, the exact molecular mechanism of PAXIP1‐AS1 in PAH pathogenesis remains largely unknown. In this study, in vivo rat PAH model was established by monocrotaline (MCT) induction and hypoxia was used to induce in vitro PAH model using human pulmonary artery smooth muscle cells (hPASMCs). Histological examinations including H&E, Masson's trichrome staining and immunohistochemistry were subjected to evaluate the pathological changes of lung tissues. Expression patterns of PAXIP1‐AS1 and RhoA were assessed using qRT‐PCR and Western blotting, respectively. CCK‐8, BrdU assay and immunofluorescence of Ki67 were performed to measure the cell proliferation. Wound healing and transwell assays were employed to evaluate the capacity of cell migration. Dual‐luciferase reporter assay, co‐immunoprecipitation, RIP and CHIP assays were employed to verify the PAXIP1‐AS1/ETS1/WIPF1/RhoA regulatory network. It was found that the expression of PAXIP1‐AS1 and RhoA was remarkably higher in both lung tissues and serum of MCT‐induced PAH rats, as well as in hypoxia‐induced hPASMCs. PAXIP1‐AS1 knockdown remarkably suppressed hypoxia‐induced cell viability and migration of hPASMCs. PAXIP1‐AS1 positively regulated WIPF1 via recruiting transcriptional factor ETS1, of which knockdown reversed PAXIP1‐AS1‐mediated biological functions. Co‐immunoprecipitation validated the WIPF1/RhoA interaction. In vivo experiments further revealed the role of PAXIP1‐AS1 in PAH pathogenesis. In summary, lncRNA PAXIP1‐AS1 promoted cell viability and migration of hPASMCs via ETS1/WIPF1/RhoA, which might provide a potential therapeutic target for PAH treatment.

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“…Kinase profiling has indicated that the earlier first-generation ROCK inhibitors have significant off-target effects, likely because fasudil and hydroxyfasudil both target the ATP binding domain, which is 100% identical for both ROCK isozymes. The pharmacological effect of earlier ROCK inhibitors is also complicated by the potentially undesirable effects of ROCK1 inhibition (which include reduced blood pressure, increased heart rate and reversible reduction in lymphocyte counts) (57, 58). More recently, better, isozyme-specific inhibitors have been formulated, such as belumosudil (KD025) (59–61) and many others (62).…”

Section: Discussionmentioning

confidence: 99%

Drug and siRNA screens identify ROCK2 as a therapeutic target for ciliopathies

Lake¹,

Smith²,

Natarajan³

et al. 2020

Preprint

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Primary cilia are microtubule-based organelles that act as cellular antennae to mediate vertebrate development and growth factor signalling. Defects in primary cilia result in a group of inherited developmental conditions known as ciliopathies. Ciliopathies often present with cystic kidney disease, a major cause of early renal failure that requires renal replacement therapies. Currently, only one drug, Tolvaptan, is licensed to slow the decline of renal function for the ciliopathy polycystic kidney disease. Novel therapeutic interventions for these conditions remain a pressing clinical need.We screened clinical development compounds for positive effects on cilia formation and function and identified fasudil hydrochloride as the top hit. Fasudil is a generic, off-patent drug that is a potent but broadly selective Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor. In a parallel whole genome siRNA-based reverse genetics phenotypic screen of positive modulators of cilia formation, we identified ROCK2 as the target molecule. We demonstrate that ROCK2 is a key mediator of cilium formation and function through effects on actin cytoskeleton remodelling. Our results indicate that specific ROCK2 inhibitors such as belumosudil (KD-025) could be repurposed for pharmacological intervention in cystic kidney disease. We propose that ROCK2 inhibition represents a novel, disease-modifying therapeutic approach for heterogeneous ciliopathies.

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Novel ROCK inhibitors for the treatment of pulmonary arterial hypertension

Cited by 32 publications

References 17 publications

ROCK Inhibition Promotes Attachment, Proliferation, and Wound Closure in Human Embryonic Stem Cell–Derived Retinal Pigmented Epithelium

ROCK Inhibition Promotes Attachment, Proliferation, and Wound Closure in Human Embryonic Stem Cell–Derived Retinal Pigmented Epithelium

LncRNA PAXIP1‐AS1 fosters the pathogenesis of pulmonary arterial hypertension via ETS1/WIPF1/RhoA axis

Drug and siRNA screens identify ROCK2 as a therapeutic target for ciliopathies

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