ROCK-2-selective targeting and its therapeutic outcomes

Sharma, Prasanti; Roy, Kalyan

doi:10.1016/j.drudis.2019.11.017

Cited by 24 publications

(14 citation statements)

References 124 publications

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“…Therefore, the usefulness of ROCK inhibitors as pulmonary artery vasodilators was demonstrated by their activity using different vasoconstrictor stimuli [35][36][37]. VSMCspecific ROCK2 knockdown mice displayed preserved RV systolic pressure after exposure to hypoxia, indicating an important role for ROCK2 in vasoconstriction induced by PH, as previously indicated by increased serum ROCK2 activity in PH patients [32,33,38,39].…”

Section: Vascular Smooth Muscle Cells (Vsmc)mentioning

confidence: 68%

“…Sustained vasoconstriction in response to endogenous chemical (vasoconstrictors, hypoxia) or physical stimuli (stretching) can explain the increased vascular tone in pulmonary arteries. In VSMCs, the activation of ROCK by agonists such as angiotensin-II, endothelin-1 and thromboxane A2, leads to MLCP inhibition and enhances the contraction at the submaximal intracellular Ca 2+ concentration (calcium sensitization) [ 31 , 32 , 33 ]. This mechanism also contributes to tone control in response to hypoxia (hypoxic pulmonary vasoconstriction) or increased intraluminal pressure (myogenic tone) [ 31 , 32 ].…”

Section: Cellular Effects Of Rock On the Cardiovascular Systemmentioning

confidence: 99%

“…In VSMCs, the activation of ROCK by agonists such as angiotensin-II, endothelin-1 and thromboxane A2, leads to MLCP inhibition and enhances the contraction at the submaximal intracellular Ca 2+ concentration (calcium sensitization) [ 31 , 32 , 33 ]. This mechanism also contributes to tone control in response to hypoxia (hypoxic pulmonary vasoconstriction) or increased intraluminal pressure (myogenic tone) [ 31 , 32 ]. In addition, the relation between ROCK and hypoxia inducible factor (HIF)-1α may further aggravate pulmonary vasoconstriction [ 34 ].…”

Section: Cellular Effects Of Rock On the Cardiovascular Systemmentioning

confidence: 99%

“…The endothelial dysfunction seen in PH involves lower nitric oxide (NO) production by the reduced expression and activation of endothelial NO synthase (eNOS) [ 23 ]. Gene knockdown of ROCK or its inhibition can upregulate eNOS expression in ECs by controlling the degradation of NOS3 mRNA [ 23 , 32 , 52 ]. Moreover, the inhibition of ROCK also increases eNOS phosphorylation by Akt, enhancing its catalytic activity, presumably by reducing the activation of phosphatase and tensin homologue (PTEN) [ 23 , 48 , 54 ].…”

Section: Cellular Effects Of Rock On the Cardiovascular Systemmentioning

confidence: 99%

“…ROCK activation plays an important role because the use of fasudil or Y-27632 abolished EC activation and leukocyte adhesion and migration [ 56 , 57 ]. Thrombin and inflammatory cytokines produced, respectively, by platelets and immune cells may increase ROCK activity in ECs, establishing a positive feedback, which exacerbates endothelial inflammation [ 32 , 43 ].…”

Section: Cellular Effects Of Rock On the Cardiovascular Systemmentioning

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: Vascular Smooth Muscle Cells (Vsmc)mentioning

confidence: 68%

Section: Cellular Effects Of Rock On the Cardiovascular Systemmentioning

confidence: 99%

Section: Cellular Effects Of Rock On the Cardiovascular Systemmentioning

confidence: 99%

Section: Cellular Effects Of Rock On the Cardiovascular Systemmentioning

confidence: 99%

Section: Cellular Effects Of Rock On the Cardiovascular Systemmentioning

confidence: 99%

See 3 more Smart Citations

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

Montagnoli

Sudo

et al. 2021

Cells

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Recent advances in the development of Rho kinase inhibitors (2015–2021)

Yao

2023

Medicinal Research Reviews

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Rho‐associated coiled‐coil kinases (ROCKs) are key downstream effectors of small GTPases. ROCK plays a central role in diverse cellular events with accumulating evidence supporting the concept that ROCK is important in tumor development and progression. Numerous ROCK inhibitors have been investigated for their therapeutic potential in the treatment of cancers. In this article, we review recent research progress on ROCK inhibitors, especially those with potential for the treatment of cancers, reported in the literature from 2015 to 2021. Most ROCK inhibitors show potent in vitro and in vivo antitumor activities and have potential in the treatment of cancers.

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Rho Kinases in Embryonic Development and Stem Cell Research

Shi

Wei

2022

Arch. Immunol. Ther. Exp.

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The Rho-associated coiled-coil containing kinases (ROCKs or Rho kinases) belong to the AGC (PKA/PKG/PKC) family of serine/threonine kinases and are major downstream effectors of small GTPase RhoA, a key regulator of actin-cytoskeleton reorganization. The ROCK family contains two members, ROCK1 and ROCK2, which share 65% overall identity and 92% identity in kinase domain. ROCK1 and ROCK2 were assumed to be functionally redundant, based largely on their major common activators, their high degree kinase domain homology, and study results from overexpression with kinase constructs or chemical inhibitors. ROCK signaling research has expanded to all areas of biology and medicine since its discovery in 1996. The rapid advance is befitting ROCK’s versatile functions in modulating various cell behavior, such as contraction, adhesion, migration, proliferation, polarity, cytokinesis, and differentiation. The rapid advance is noticeably driven by an extensive linking with clinical medicine, including cardiovascular abnormalities, aberrant immune responsive, and cancer development and metastasis. The rapid advance during the past decade is further powered by novel biotechnologies including CRISPR-Cas and single cell omics. Current consensus, derived mainly from gene targeting and RNA interference approaches, is that the two ROCK isoforms have overlapping and distinct cellular, physiological and pathophysiology roles. In this review, we present an overview of the milestone discoveries in ROCK research. We then focus on the current understanding of ROCK signaling in embryonic development, current research status using knockout and knockin mouse models, and stem cell research.

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ROCK-2-selective targeting and its therapeutic outcomes

Cited by 24 publications

References 124 publications

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

Recent advances in the development of Rho kinase inhibitors (2015–2021)

Rho Kinases in Embryonic Development and Stem Cell Research

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