ROCK as a therapeutic target for ischemic stroke

Sladojević, Nikola; Yu, Brian; Liao, James K.

doi:10.1080/14737175.2017.1395700

Cited by 44 publications

(30 citation statements)

References 101 publications

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“…Fasudil and Y27632 are widely used nonselective ROCK inhibitors. These inhibitors target ROCK's ATP-dependent kinase domain and are equipotent in inhibiting both isoforms [17]. Due to these limitations and the nonselectivity of ROCK inhibitors, fasudil is the only ROCK inhibitor approved for human use in Japan and Quantitative analysis of the number of surviving neurons from ICH and ICH/HF rat brains in the perihematomal area at each time point.…”

Section: Discussionmentioning

confidence: 99%

Hydrochloride fasudil attenuates brain injury in ICH rats

Liu

Lou

Zhang

et al. 2020

Translational Neuroscience

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AbstractAimThe aim of this study was to investigate the neuroprotective effects of hydrochloride fasudil (HF) in rats following intracerebral hemorrhage (ICH).MethodsMale Wistar rats were randomly divided into four groups: normal, sham-operated, ICH, and ICH/HF. ICH was induced by injection of non-anticoagulant autologous arterial blood into the right caudate nucleus. The levels of Rho-associated protein kinase 2 (ROCK2) mRNA and protein around the site of the hematoma were measured by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA), respectively. The levels of interleukin-6 and tumor necrosis factor-α in serum were detected by ELISA. The inflammatory cells and changes in the neuronal morphology around the hematoma were visualized using hematoxylin and eosin and Nissl staining. Brain edema was measured by comparing wet and dry brain weights.ResultsFollowing ICH, the levels of ROCK2 were significantly increased from day 1 to day 7. The levels of ROCK2 were significantly lower in rats treated with HF than in controls. The levels of inflammatory cytokines and brain water content were significantly higher in rats treated with HF than in controls. Administration of HF significantly reduced the levels of inflammatory cytokines and brain water content from day 1 to day 7. In the acute phase of ICH, a large number of neutrophils infiltrated the perihematomal areas. In comparison with the ICH group, the ICH/HF group showed markedly fewer infiltrating neutrophils on day 1. Nissl staining showed that ICH caused neuronal death and loss of neurons in the perihematomal areas at all time points and that treatment with HF significantly attenuated neuronal loss.ConclusionsHF exerts neuroprotective effects in ICH rats by inhibiting the expression of ROCK2, reducing neutrophil infiltration and production of inflammatory cytokines, decreasing brain edema, and attenuating loss of neurons.

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Section: Discussionmentioning

confidence: 99%

Hydrochloride fasudil attenuates brain injury in ICH rats

Liu

Lou

Zhang

et al. 2020

Translational Neuroscience

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“…In the present study, an important mechanism was revealed as miR-335 was observed to regulate SG formation by targeting the mRNA of ROCK2. Bioinformatics analysis predicted that ROCK2 mRNA is targeted by miR-335 and ROCK2 served an important role in ischemic stroke (45,46). ROCKs can lead to the phosphorylation of downstream substrates and induce alterations in cellular function.…”

Section: Discussionmentioning

confidence: 99%

miR‑335 promotes stress granule formation to inhibit apoptosis by targeting ROCK2 in acute ischemic stroke

Ren

et al. 2019

Int J Mol Med

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Under harmful environmental conditions, stress granules (SGs), macromolecular aggregates that are associated with cell survival and death, are produced in the eukaryotic cytoplasm. However, whether and how microRNAs (miRNAs/miRs) modulate SG formation induced by acute ischemic stroke has not been investigated. In the present study, a rat model of middle cerebral artery occlusion (MCAO) was utilized and miRNA array profiling and reverse transcription-quantitative polymerase chain reaction were performed. The results revealed that miR-335 was downregulated during acute ischemic stroke, which was concomitant with reduced SG formation, enhanced apoptosis levels and increased Rho associated protein kinase 2 (ROCK2) expression. In the MCAO rat and serum-free cell models, miR-335 treatment upregulated SG formation, alleviated the ischemia-induced infarction, and decreased ROCK2 protein expression and apoptosis levels. By contrast, when compared with miR-335 treatment, the inhibition of miR-335 resulted in reduced SG formation and higher ROCK2 expression and apoptosis levels. Target prediction analysis and luciferase 3′-untranslated region reporter assay identified ROCK2 as the direct target of miR-335. Furthermore, ROCK2 silencing enhanced SG formation and attenuated the level of apoptosis in the serum-free cell model. In addition, ROCK2 silencing markedly inhibited the effect of miR-335 on SG formation and apoptosis levels. Unexpectedly, the phosphorylation of T-cell intracellular antigen-1 was significantly inhibited by miR-335 in the MCAO rat model, which provides a reasonable explanation for the promotional effect of miR-335 on SG formation by specifically targeting ROCK2. In conclusion, these results demonstrate that miR-335 promotes SG formation and inhibits apoptosis by reducing ROCK2 expression in acute ischemic stroke, which provides a possible therapeutic target for brain injury.

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“…ROCK modulates actin filament assembly resulting in force generation and cell adhesion, migration and phagocytosis. The activation of ROCK is also involved in the contraction of the actomyosin ring and in the intermediate filaments disorder during cytokinesis [ 26 , 27 ]. Besides the assembly of F-actin stress fibers, ROCK also mediates the release of transcription factors such as myocardin-related transcription factor (MRTF) and yes-associated protein (YAP), promoting changes in gene expression and phenotypic changes [ 26 , 27 ].…”

Section: Overview On Rock Structure and Functionsmentioning

confidence: 99%

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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ROCK as a therapeutic target for ischemic stroke

Cited by 44 publications

References 101 publications

Hydrochloride fasudil attenuates brain injury in ICH rats

Hydrochloride fasudil attenuates brain injury in ICH rats

miR‑335 promotes stress granule formation to inhibit apoptosis by targeting ROCK2 in acute ischemic stroke

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

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