Protective effect of fasudil, a Rho-kinase inhibitor, on chemokine expression, leukocyte recruitment, and hepatocellular apoptosis in septic liver injury

Thorlacius, Karin; Slotta, Jan E.; Laschke, Matthias W.; Wang, Yusheng; Menger, Michael D.; Jeppsson, Bengt; Thorlacius, Henrik

doi:10.1189/jlb.0705406

Cited by 66 publications

(59 citation statements)

References 36 publications

(56 reference statements)

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“…These include redox signaling through NADPH oxidase (37), secretion of signaling molecules (38), and adhesion of leukocytes (14). Our in vivo results were notable for the ability of Ang-1 to block endotoxin-induced infiltration of leukocytes into the lung parenchyma.…”

Section: Discussionsupporting

confidence: 49%

“…Rac1 and RhoA are known to mediate opposing changes in EC permeability (the former increasing barrier function and the latter reducing barrier function) induced by a number of ligands (12). Endotoxin increases vascular permeability by activating RhoA (13,14). Rho activity is regulated, in part, by the * This work was supported by seed funds from Beth Israel Deaconess Medical Center (to V. P. S.) and National Institutes of Health Grants CA45548 and CA55833 (to D. E.…”

mentioning

confidence: 99%

“…Rac1 and RhoA are known to mediate opposing changes in EC permeability (the former increasing barrier function and the latter reducing barrier function) induced by a number of ligands (12). Endotoxin increases vascular permeability by activating RhoA (13,14). Rho activity is regulated, in part, by the inhibitory GTPase activating protein, p190 RhoGAP (15).…”

mentioning

confidence: 99%

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Angiopoietin-1 Requires p190 RhoGAP to Protect against Vascular Leakage in Vivo

Mammoto¹,

Parikh²,

Mammoto

et al. 2007

Journal of Biological Chemistry

162

219

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Angiopoietin-1 (Ang-1), a ligand of the endothelium-specific receptor Tie-2, inhibits permeability in the mature vasculature, but the mechanism remains unknown. Here we show that Ang-1 signals Rho family GTPases to organize the cytoskeleton into a junction-fortifying arrangement that enhances the permeability barrier function of the endothelium. Ang-1 phosphorylates Tie-2 and its downstream effector phosphatidylinositol 3-kinase. This induces activation of one endogenous GTPase, Rac1, and inhibition of another, RhoA. Loss of either part of this dual effect abrogates the cytoskeletal and anti-permeability actions of Ang-1, suggesting that coordinated GTPase regulation is necessary for the vessel-sealing effects of Ang-1. p190 RhoGAP, a GTPase regulatory protein, provides this coordinating function as it is phosphorylated by Ang-1 treatment, requires Rac1 activation, and is necessary for RhoA inhibition. Ang-1 prevents the cytoskeletal and pro-permeability effects of endotoxin but requires p190 RhoGAP to do so. Treatment with p190 RhoGAP small interfering RNA completely abolishes the ability of Ang-1 to rescue endotoxemia-induced pulmonary vascular leak and inflammation in mice. We conclude that Ang-1 prevents vascular permeability by regulating the endothelial cytoskeleton through coordinated and opposite effects on the Rho GTPases Rac1 and RhoA. By linking Rac1 activation and RhoA inhibition, p190 RhoGAP is critical to the protective effects of Ang-1 against endotoxin. These results provide mechanistic evidence that targeting the endothelium through Tie-2 may offer specific therapeutic strategies in life-threatening endotoxemic conditions such as sepsis and acute respiratory distress syndrome. Angiopoietin-1 (Ang-1)3 is a 498-amino acid secreted glycoprotein whose germ line depletion leads to several cardiovascular defects that result in embryonic lethality (1, 2). Although made by numerous cell types, the actions of Ang-1 are primarily mediated by a receptor tyrosine kinase, Tie-2, whose expression is largely restricted to endothelial cells (ECs). Critical roles for Ang-1 and Tie-2 have been described in the formation of the primitive cardiac tube and embryonic vasculature (3). Although necessary for developmental angiogenesis to occur, Ang-1 expression and Tie-2 phosphorylation persist into adulthood in organs not considered angiogenically active (4), suggesting a nonangiogenic role in the mature vasculature. In fact, Ang-1 has been shown to protect adult blood vessels against plasma leakage because of vascular endothelial growth factor or mustard oil (5, 6). However, the mechanism by which Ang-1 defends against vascular leakage in vivo has remained largely unknown.Permeability is a tightly regulated feature of all vascular beds. A systemic increase in permeability, leading to a degree of vascular leak that impairs organ function, is a hallmark of sepsis, a lethal syndrome of multiorgan dysfunction that arises as a result of disseminated infection. We have previously shown that Tie-2 inhibition induces changes...

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Section: Discussionsupporting

confidence: 49%

mentioning

confidence: 99%

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Angiopoietin-1 Requires p190 RhoGAP to Protect against Vascular Leakage in Vivo

Mammoto¹,

Parikh²,

Mammoto

et al. 2007

Journal of Biological Chemistry

162

219

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“…Caspase-mediated cleavage of ROCK1 is known to induce membrane blebbing, nuclear fragmentation and packaging of nuclear material into blebs at the cell surface and treatment of cells with the ROCKI/II inhibitor, Y-27632, has been shown to prevent ROCK1-induced membrane blebbing (Coleman et al, 2001;Sebbagh et al, 2001). Similarly, Y-27632 has also been shown to protect U2OS cells from camptothecin-induced apoptosis and reduce endotoxininduced apoptosis in the liver (Ongusaha et al, 2006;Thorlacius et al, 2006). Rnd3 is a known substrate for ROCK1 and we observe that, in addition to protecting cells from apoptosis, prolonged treatment with Y-27632 also results in a decrease in Rnd3 expression.…”

Section: Discussionmentioning

confidence: 99%

Plakoglobin-dependent regulation of keratinocyte APOPTOSIS by Rnd3

Ryan

Lock

Heath

et al. 2012

Journal of Cell Science

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SummaryThe human epidermis is a self-renewing, stratified epithelial tissue that provides the protective function of the skin. The principal cell type within the epidermis is the keratinocyte, and normal function of the epidermis requires that keratinocyte proliferation, differentiation and cell death be carefully controlled. There is clear evidence that signalling through adhesion receptors such as integrins and cadherins plays a key role in regulating epidermal function. Previous work has shown that Rho family GTPases regulate cadherinand integrin-based adhesion structures and hence epidermal function. In this study, we show that a member of this family, Rnd3, regulates desmosomal cell-cell adhesion in that loss of Rnd3 expression leads to an increase in desmosomes at sites of cell-cell adhesion and altered colony morphology. Loss of Rnd3 expression is also associated with resistance to cisplatin-mediated apoptosis in keratinocytes and this resistance is mediated through the desmosomal protein plakoglobin. We propose a novel plakoglobin-dependent role for Rnd3 in the regulation of keratinocyte cell death.

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“…ROCK mediates production of reactive oxygen species and inflammatory cytokines which are substantially involved in the pathogenesis of hepatocellular necrosis and apoptosis induced by cold ischemia-reperfusion injury after liver transplantation in rats [125]. 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].…”

Section: In Vivo Evidencementioning

confidence: 99%

Rho kinase in the regulation of cell death and survival

Shi

Wei

2007

Arch. Immunol. Ther. Exp.

219

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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Protective effect of fasudil, a Rho-kinase inhibitor, on chemokine expression, leukocyte recruitment, and hepatocellular apoptosis in septic liver injury

Cited by 66 publications

References 36 publications

Angiopoietin-1 Requires p190 RhoGAP to Protect against Vascular Leakage in Vivo

Angiopoietin-1 Requires p190 RhoGAP to Protect against Vascular Leakage in Vivo

Plakoglobin-dependent regulation of keratinocyte APOPTOSIS by Rnd3

Rho kinase in the regulation of cell death and survival

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