Inhibition of Rho-kinase protects the heart against ischemia/reperfusion injury

Bao, Weike

doi:10.1016/j.cardiores.2003.12.004

Cited by 199 publications

(182 citation statements)

References 36 publications

(39 reference statements)

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“…In particular, there is substantial evidence that Rho GTPases are involved in synaptic remodeling and maintenance (Govek et al, 2005), and relative changes in their active/inactive state are associated with dendritic plasticity (Nakayama et al, 2000;Pilpel et al, 2004). Moreover, inhibition of Rho GTPases or their effectors protects against ischemia/reperfusion injury in vivo in both brain (Laufs et al, 2000;Trapp et al, 2001) and other tissues (Bao et al, 2004). Based on these findings, we offer the speculation that modulation of Rho GTPase signaling cascades by Slit has the net effect of maintaining cellular integrity and functioning in ischemic brain secondary to its ability to prevent or reduce synaptic disruption and other changes in dendritic morphology crucial to neuronal viability (Hasbani et al, 2001;Park et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

Altay

McLaughlin

et al. 2007

Experimental Neurology

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Cerebrovascular inflammation contributes to secondary brain injury following ischemia. Recent in vitro studies of cell migration and molecular guidance mechanisms have indicated that the Slit family of secreted proteins can exert repellant effects on leukocyte recruitment in response to chemoattractants. Utilizing intravital microscopy, we addressed the role of Slit in modulating leukocyte dynamics in the mouse cortical venular microcirculation in vivo following TNFα application or global cerebral ischemia. We also studied whether Slit affected neuronal survival in the mouse global ischemia model as well as in mixed neuronal-glial cultures subjected to oxygenglucose deprivation. We found that systemically administered Slit significantly attenuated cerebral microvessel leukocyte-endothelial adherence occurring 4 h after TNFα and 24 h after global cerebral ischemia. Administration of RoboN, the soluble receptor for Slit, exacerbated the acute chemotactic response to TNFα. These findings are indicative of a tonic repellant effect of endogenous Slit in brain under acute proinflammatory conditions. Three days of continuous systemic administration of Slit following global ischemia significantly attenuated the delayed neuronal death of hippocampal CA1 pyramidal cells. Moreover, Slit abrogated neuronal death in mixed neuronal-glial cultures exposed to oxygen-glucose deprivation. The ability of Slit to reduce the recruitment of immune cells to ischemic brain and to provide cytoprotective effects suggests that this protein may serve as a novel anti-inflammatory and neuroprotective target for stroke therapy.

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Section: Discussionmentioning

confidence: 99%

Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

Altay

McLaughlin

et al. 2007

Experimental Neurology

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“…Ischemia-reperfusion injury increased RhoA expression and ROCK activity in ischemic myocardium and treatment with Y-27632 protects against ischemiareperfusion injury [96]. Y-27632 decreased infarct size and improved cardiac function by inhibiting myocardial apoptosis and inflammatory responses, in part by preventing Bcl-2 downregulation and blocking proinflammatory cytokine production.…”

Section: Rock In Heart Diseasesmentioning

confidence: 94%

“…ROCK is also activated in murine hearts following myocardial ischemia-reperfusion injury [96] and infarction [97]. Ischemia-reperfusion injury increased RhoA expression and ROCK activity in ischemic myocardium and treatment with Y-27632 protects against ischemiareperfusion injury [96].…”

Section: Rock In Heart Diseasesmentioning

confidence: 99%

ROCKs as therapeutic targets in cardiovascular diseases

Rikitake

Liao

2005

Expert Review of Cardiovascular Therapy

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There is growing evidence that Rho-kinases (ROCKs), the immediate downstream targets of the small guanosine triphosphate-binding protein Rho, may contribute to cardiovascular disease. ROCKs play a central role in diverse cellular functions such as smooth muscle contraction, stress fiber formation and cell migration and proliferation. Overactivity of ROCKs is observed in cerebral ischemia, coronary vasospasm, hypertension, vascular inflammation, arteriosclerosis and atherosclerosis. ROCKs, therefore, may be an important and still relatively unexplored therapeutic target in cardiovascular disease. Recent experimental and clinical studies using ROCK inhibitors such as Y-27632 and fasudil have revealed a critical role of ROCKs in embryonic development, inflammation and oncogenesis. This review will focus on the potential role of ROCKs in cellular functions and discuss the prospects of ROCK inhibitors as emerging therapy for cardiovascular diseases. Keywords contraction; endothelium; hypertension; inflammation; leukocyte; remodeling; Rho-kinase; smooth muscleThe small guanosine triphosphate (GTP)-binding proteins belonging to the Rho family regulate various aspects of cell shape, motility, proliferation and apoptosis [1]. Rho-kinases (ROCKs), which were one of the first downstream effectors of Rho to be discovered [2-4], were found to mediate RhoA-induced actin cytoskeletal changes through effects on myosin light-chain (MLC) phosphorylation [5,6]. ROCKs are protein serine/threonine kinases that share 45-50% homology with other actin cytoskeletal kinases such as myotonic dystrophy kinase (DMPK), myotonic dystrophy-related cdc42-binding kinase (MRCK) and citron kinase [1]. ROCKs consist of an amino-terminal kinase domain, followed by a mid-coiled-coil-forming region containing a Rho-binding domain (RBD) and a carboxy-terminal cysteine-rich domain (CRD) located within the pleckstrin homology (PH) motif (FIGURE 1). In mammalian systems, two ROCK isoforms have been identified. ROCK1, which is also known as ROKβ, and p160ROCK, which is located on chromosome 18 and encodes a 1354 amino acid protein [4,5]. ROCK2, which is also known as ROKα and sometimes confusingly called Rho-kinase, is located on chromosome 12 and contains 1388 amino acids [2,7,8]. ROCK1 and 2 share an overall 65% homology in amino acid sequence and 92% homology in their kinase domains

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“…ROCK mediates infiltration of leukocytes as well as production of TNFα and CXC chemokines and hepatocellular apoptosis in endotoxemic liver injury (challenged with lipopolysaccharide and D-galactosamine) [134]. The inhibition of ROCK by Y27632 during acute ischemia/reperfusion injury significantly reduces cardiomyocyte apoptosis, prevents down-regulation of Bcl-2 protein, and attenuates inflammatory responses [8]. ROCK inhibition by fasudil reduces endothelin-1-induced myocardial injury, such as multifocal myocardial necrosis with infiltration of neutrophils and macrophages in the rabbit [149].…”

Section: In Vivo Evidencementioning

confidence: 99%

Rho kinase in the regulation of cell death and survival

Shi

Wei

2007

Arch. Immunol. Ther. Exp.

211

183

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SummaryRho kinase (ROCK) belongs to a family of serine/threonine kinases that are activated via interaction with Rho GTPases. ROCK is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, and proliferation. Recent studies have shown that ROCK plays an important role in the regulation of apoptosis in various cell types and animal disease models. Two ROCK isoforms, ROCK1 and ROCK2, are assumed to be function redundant, based largely on kinase construct overexpression, and chemical inhibitors (Y27632 and fasudil), which inhibit both ROCK1 and ROCK2. Gene targeting and RNA interference approaches allow further dissection of distinct cellular, physiological and patho-physiological functions of the two ROCK isoforms. This review, based on recent molecular, cellular and animal studies, focuses on the current understanding of ROCK signaling in the regulation of apoptosis and highlights the new findings from recently generated ROCK-deficient mice.

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Inhibition of Rho-kinase protects the heart against ischemia/reperfusion injury

Cited by 199 publications

References 36 publications

Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

ROCKs as therapeutic targets in cardiovascular diseases

Rho kinase in the regulation of cell death and survival

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