The Kinase Inhibitor Fasudil (HA-1077) Reduces Intimal Hyperplasia through Inhibiting Migration and Enhancing Cell Loss of Vascular Smooth Muscle Cells

Negoro, Nobuyuki; Hoshiga, Masaaki; Seto, Minoru; Kohbayashi, Eiko; Fukui, Ryosuke; Shibata, Nobuhiko; Nakakoji, Takahiro; Nishiguchi, Futoshi; Sasaki, Yasuharu; Ishihara, Tadashi; Ohsawa, Nakaaki

doi:10.1006/bbrc.1999.1129

Cited by 48 publications

(37 citation statements)

References 25 publications

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“…Rho-kinase inhibitors reduce neointimal formation induced by balloon injury in rat (420,444) and pig (114,332) or by stent implantation in pig (301). In these models, both an antiproliferative action through downregulation of the cyclin-dependent kinase inhibitor p27…”

Section: Rho Proteinsmentioning

confidence: 99%

Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

Loirand

Sauzeau

Pacaud

2013

Physiological Reviews

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Small G proteins exist in eukaryotes from yeast to human and constitute the Ras superfamily comprising more than 100 members. This superfamily is structurally classified into five families: the Ras, Rho, Rab, Arf, and Ran families that control a wide variety of cell and biological functions through highly coordinated regulation processes. Increasing evidence has accumulated to identify small G proteins and their regulators as key players of the cardiovascular physiology that control a large panel of cardiac (heart rhythm, contraction, hypertrophy) and vascular functions (angiogenesis, vascular permeability, vasoconstriction). Indeed, basal Ras protein activity is required for homeostatic functions in physiological conditions, but sustained overactivation of Ras proteins or spatiotemporal dysregulation of Ras signaling pathways has pathological consequences in the cardiovascular system. The primary object of this review is to provide a comprehensive overview of the current progress in our understanding of the role of small G proteins and their regulators in cardiovascular physiology and pathologies.

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Section: Rho Proteinsmentioning

confidence: 99%

Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

Loirand

Sauzeau

Pacaud

2013

Physiological Reviews

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“…A less specific Rho-kinase inhibitor than Y27632, fasudil, which is known to be an MLC kinase inhibitor, inhibited migration of cultured rabbit SMCs and reduced neointima formation by enhancing SMC loss without affecting cell proliferation in balloon-injured rabbit carotid artery. 26 In porcine coronary artery showing the inflammatory/arteriosclerotic remodeling induced by interleukin-1␤ treatment, increased Rho-kinase activity was documented, and hydroxyfasudil, a derivative of fasudil, suppressed serotonin-induced vasospasm at the remodeling site. 27 This, taken together with the present study using a more specific Rho-kinase inhibitor, Y27632, 12 indicates that the Rho-kinase-mediated pathway may play important roles in vascular responses to various kinds of vascular injury that is implicated in the pathogenesis of arteriosclerosis through the mechanisms of not only vascular remodeling but also vasomotion control.…”

Section: Neointimal Lesion At Day 4 After Vascular Injurymentioning

confidence: 99%

Role of Rho-Associated Kinase in Neointima Formation After Vascular Injury

et al. 2001

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Background —The Rho/Rho-associated kinase (Rho-kinase) system is implicated in various cellular functions, including migration, proliferation, and apoptosis. Because a possible role of the system is suggested in neointima formation after vascular injury, we sought to examine whether a new specific Rho-kinase inhibitor, Y27632, prevents neointima formation of the balloon-injured rat carotid artery, and if so, to investigate the effects of Y27632 on migration, proliferation, and apoptosis of smooth muscle cells (SMCs) in the injured artery. Methods and Results —Y27632 was administered intraperitoneally from 1 day before to 14 days after vascular injury. Treatment with Y27632 inhibited phenylephrine-induced Rho-kinase activation in the carotid artery on the basis of immunoblotting against the phosphorylated myosin-binding subunit of myosin phosphatase. Y27632 markedly prevented neointima formation at days 7 and 14. In controls, BrdU + proliferating and TUNEL + apoptotic SMCs were transiently and coincidentally increased in the neointima, with a peak at day 7. Y27632 significantly increased the neointimal TUNEL + SMCs at days 7 and 14, but not BrdU + SMCs. Y27642 significantly decreased the number of intimal SMCs at day 4, while not affecting the number of BrdU + or TUNEL + SMCs. Reendothelialization after balloon injury was not significantly affected by Y27632 at days 7 and 14. Conclusions —Y27632 inhibited neointima formation by enhancing SMC apoptosis and probably by suppressing early SMC migration. Therefore, a role of Rho-kinase is suggested in neointima formation after vascular injury.

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“…26 In brief, for BrdU immunohistochemistry, rats were intraperitoneally injected with 100 mg/kg BrdU at 24 hours and 1 hour before being killed. In the same way as the estimation of I/M ratio, the left carotid arteries were fixed by perfusion of 10% (wt/vol) formaldehyde for 15 minutes, removed, embedded in paraffin, and sectioned at 3-m thickness.…”

Section: Brdu Immunohistochemistry and Morphometric Analysesmentioning

confidence: 99%

Gene Transfer of Dominant-Negative Mutants of Extracellular Signal–Regulated Kinase and c-Jun NH2-Terminal Kinase Prevents Neointimal Formation in Balloon-Injured Rat Artery

Izumi

Kim

Namba

et al. 2001

Circulation Research

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113

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Abstract-We previously reported that extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK), belonging to mitogen-activated protein kinases, are rapidly activated in balloon-injured artery. Therefore, we examined the role of these kinase activations in neointimal formation by using an in vivo gene transfer technique. We made the dominant-negative mutants of ERK (DN-ERK) and JNK (DN-JNK) to specifically inhibit endogenous ERK and JNK activation, respectively. Before balloon injury, these mutants were transfected into rat carotid artery using the hemagglutinating virus of Japan liposome method. In vivo transfection of DN-ERK and DN-JNK significantly suppressed the activation of ERK and JNK, respectively, after balloon injury, confirming successful expression of the transfected genes. Neointimal formation at 14 and 28 days after injury was prevented by gene transfer of DN-ERK or DN-JNK. Furthermore, bromodeoxyuridine labeling index and total cell-counting analysis at 7 days showed that either DN-ERK or DN-JNK remarkably suppressed smooth muscle cell (SMC) proliferation in both the intima and the media after injury. Gene transfer of wild-type ERK (W-ERK) or JNK (W-JNK) significantly enhanced neointimal hyperplasia at 14 days after injury. Furthermore, DN-ERK and DN-JNK significantly suppressed serum-induced SMC proliferation in vitro. We obtained the first evidence that in vivo gene transfer of DN-ERK or DN-JNK prevented neointimal formation in balloon-injured artery by inhibiting SMC proliferation. Thus, ERK and JNK activation triggers SMC proliferation, leading to neointimal formation. These kinases may be the new therapeutic targets for prevention of vascular diseases.

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The Kinase Inhibitor Fasudil (HA-1077) Reduces Intimal Hyperplasia through Inhibiting Migration and Enhancing Cell Loss of Vascular Smooth Muscle Cells

Cited by 48 publications

References 25 publications

Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

Role of Rho-Associated Kinase in Neointima Formation After Vascular Injury

Gene Transfer of Dominant-Negative Mutants of Extracellular Signal–Regulated Kinase and c-Jun NH2-Terminal Kinase Prevents Neointimal Formation in Balloon-Injured Rat Artery

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