Inhibition of Rho kinases increases directional motility of microvascular endothelial cells

Breyer, Johannes; Samarin, Jana; Rehm, Margot; Lautscham, Lena; Fabry, Ben; Goppelt‐Struebe, Margarete

doi:10.1016/j.bcp.2011.12.012

Cited by 22 publications

(23 citation statements)

References 45 publications

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“…Constitutive activation of RhoGTPases was associated with TJ endocytosis and stress fibers assembly and reorganization [14,49,50]. Rhoassociated coiled-coil-containing kinases (ROCK) are important cytoskeleton regulators through downstream modulation of actin, myosin, and associated proteins [10,[49][50][51]. Previous studies have shown the involvement of the Rho/ROCK pathway on actin reorganization and verified that ROCK inhibition was able to block actin disruption [50,52].…”

Section: Discussionmentioning

confidence: 96%

“…Modulation of RhoGTPases by METH has been reported showing that RhoA, Rac, or Cdc42 can be modulated by METH, impacting the endothelial barrier [10,13,14]. Constitutive activation of RhoGTPases was associated with TJ endocytosis and stress fibers assembly and reorganization [14,49,50]. Rhoassociated coiled-coil-containing kinases (ROCK) are important cytoskeleton regulators through downstream modulation of actin, myosin, and associated proteins [10,[49][50][51].…”

Section: Discussionmentioning

confidence: 99%

“…Rhoassociated coiled-coil-containing kinases (ROCK) are important cytoskeleton regulators through downstream modulation of actin, myosin, and associated proteins [10,[49][50][51]. Previous studies have shown the involvement of the Rho/ROCK pathway on actin reorganization and verified that ROCK inhibition was able to block actin disruption [50,52]. Aiming to evaluate the role of ROCK on METH-induced structural damage, we used the ROCK selective inhibitor fasudil.…”

Section: Discussionmentioning

confidence: 99%

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Acetyl-L-Carnitine Prevents Methamphetamine-Induced Structural Damage on Endothelial Cells via ILK-Related MMP-9 Activity

et al. 2014

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Methamphetamine (METH) is a potent psychostimulant highly used worldwide. Recent studies evidenced the involvement of METH in the breakdown of the blood-brain-barrier (BBB) integrity leading to compromised function. The involvement of the matrix metalloproteinases (MMPs) in the degradation of the neurovascular matrix components and tight junctions (TJs) is one of the most recent findings in METH-induced toxicity. As BBB dysfunction is a pathological feature of many neurological conditions, unveiling new protective agents in this field is of major relevance. Acetyl-L-carnitine (ALC) has been described to protect the BBB function in different paradigms, but the mechanisms underling its action remain mostly unknown. Here, the immortalized bEnd.3 cell line was used to evaluate the neuroprotective features of ALC in METH-induced damage. Cells were exposed to ranging concentrations of METH, and the protective effect of ALC 1 mM was assessed 24 h after treatment. F-actin rearrangement, TJ expression and distribution, and MMPs activity were evaluated. Integrin-linked kinase (ILK) knockdown cells were used to assess role of ALC in ILK mediated METHtriggered MMPs' activity. Our results show that METH led to disruption of the actin filaments concomitant with claudin-5 translocation to the cytoplasm. These events were mediated by MMP-9 activation in association with ILK overexpression. Pretreatment with ALC prevented METH-induced activation of MMP-9, preserving claudin-5 location and the structural arrangement of the actin filaments. The present results support the potential of ALC in preserving BBB integrity, highlighting ILK as a new target for the ALC therapeutic use.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Acetyl-L-Carnitine Prevents Methamphetamine-Induced Structural Damage on Endothelial Cells via ILK-Related MMP-9 Activity

et al. 2014

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“…Cell migration is a key step in tissue repair and regeneration and involves recruitment of progenitor cells to injury sites. The involvement of Rho/Rock signalling pathway in mediating cell migration is evidenced during the development of various tissues including bone (Li et al 2006;Breyer et al 2012;Ichida et al 2011;Montanez et al 2009;Benoit et al 2009), and Rho/ROCK signalling inhibition can increase cell movement into bone formation sites in a mouse model of ectopic bone formation (Ichida et al 2011). In addition, a line of evidence suggests that Rho/Rock signalling plays a key role in directing osteoprogenitor cells into the osteoblast lineage in different models of osteoinduction (Shih et al 2011;Khatiwala et al 2009).…”

Section: Rho/rock Signalling Pathwaymentioning

confidence: 99%

Bone-Biomimetic Biomaterial and Cell Fate Determination

Zreiqat

2014

Mechanical Engineering Series

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Despite its remarkable capacity to undergo self-repair, bone tissue cannot regenerate across critical-sized defects, and their successful reconstruction remains a major clinical challenge. Current treatment options are limited and often associated with a high incidence of complications, which may result in non-union or re-fracture. There is a great and growing need for alternative techniques to replace, restore or regenerate damaged or diseased bone. Biomaterials-based bone tissue engineering via the use of synthetic bone substitutes represents a particularly promising alternative, which circumvents the drawbacks of conventional treatments. To achieve successful reconstructive outcomes, synthetic bone substitutes need to be biocompatible and provide necessary signals to osteoprogenitor cells to control downstream cell responses including adhesion, migration, proliferation and differentiation into osteoblasts. One feasible approach to develop synthetic bone substitutes with such biological properties is to mimic the innate physical and/or chemical properties of bone. In this chapter, we discuss the design aspects of bone-biomimetic biomaterials that provide the signals necessary for bone regeneration, and the underlying mechanisms by which bone-biomimetic biomaterials determine the fate of mesenchymal stem cells/osteoprogenitor cells. Protein adsorption to biomaterial surfaces and their subsequent influence on cell adhesion and intracellular signal transduction will be discussed in detail, with particular emphasis on the key molecules and signalling pathways involved in directing the osteogenic development of cells.

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“…It has been shown that ROCK mediates endothelial cell permeability [58,59] by regulating cell–cell tight junction [58], regulates cell adhesion between endothelial cells and extracellular matrix [60] and increases inflammatory cell infiltration [61], all of which contribute to vascular inflammation. Indeed, abnormal activation of ROCK has been shown to induce vascular inflammation [51].…”

Section: Rock-mediated Inflammation As a Risk Factor For Strokementioning

confidence: 99%

ROCKs as immunomodulators of stroke

Wang

Liao

2012

Expert Opinion on Therapeutic Targets

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Introduction Stroke is the third leading cause of death and a major cause of long-term disability in the adult population. Growing evidence suggests that inflammation may play an important role in the evolution of stroke. Because Rho-associated coiled-coil containing kinases (ROCKs) are important mediators of inflammation, they may contribute to stroke and stroke recovery. Areas covered The pathophysiological role of ROCKs in mediating inflammation at different phases of stroke, and the therapeutic opportunities for stroke prevention and stroke treatment with ROCK inhibitors will be discussed. Expert opinion Inflammation is a double-edged sword during the evolution of stroke. Immunomodulation might provide a novel therapeutic approach for stroke prevention and stroke treatment. ROCK plays an important role in mediating the inflammatory response following vascular injury as well as platelet activation and thrombus formation. ROCK inhibitors have been shown to be beneficial in stroke prevention, acute neuroprotection and chronic stroke recovery by affecting inflammatory-mediated platelet and endothelial function, smooth muscle contraction and neuronal regeneration. Thus, ROCK-mediated inflammation could be a potential therapeutic target for stroke prevention and stroke treatment. However, the mechanism by which ROCKs regulate the inflammatory response is unclear, and the role of the two ROCK isoforms in stroke and stroke recovery remains to be determined.

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Inhibition of Rho kinases increases directional motility of microvascular endothelial cells

Cited by 22 publications

References 45 publications

Acetyl-L-Carnitine Prevents Methamphetamine-Induced Structural Damage on Endothelial Cells via ILK-Related MMP-9 Activity

Acetyl-L-Carnitine Prevents Methamphetamine-Induced Structural Damage on Endothelial Cells via ILK-Related MMP-9 Activity

Bone-Biomimetic Biomaterial and Cell Fate Determination

ROCKs as immunomodulators of stroke

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