Long-Term Inhibition of Rho-Kinase Suppresses Neointimal Formation After Stent Implantation in Porcine Coronary Arteries: Involvement of Multiple Mechanisms

Matsumoto, Yasuharu; Uwatoku, Toyokazu; Oi, Keiji; Abe, Kohtaro; Hattori, Tsuyoshi; Morishige, Kunio; Eto, Yoshikatsu; Fukumoto, Yoshihiro; Nakamura, Kei; Shibata, Yosaburo; Matsuda, Takehisa; Takeshita, Akira; Shimokawa, Hiroaki

doi:10.1161/01.atv.0000105053.46994.5b

Cited by 101 publications

(59 citation statements)

References 54 publications

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“…5,30 -32 Oral administration of fasudil suppresses cardiovascular lesion formation through suppression of the expression of several cytokines, including MIF, TGF-␤, IFN-␥, monocyte chemoattractant protein-1, and angiotensin II. 20,22,32 These findings, together with the present results, suggest that fasudil could downregulate those inflammatory cytokines, resulting in the suppression of LV remodeling. Third, we were recently able to demonstrate that Rho-kinase inhibitors could ameliorate endothelial dysfunction through upregulation of endothelial NO synthase.…”

Section: Possible Mechanisms Of the Inhibitory Effects Of Fasudil On supporting

confidence: 79%

Long-Term Inhibition of Rho-Kinase Suppresses Left Ventricular Remodeling After Myocardial Infarction in Mice

et al. 2004

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Background-Rho-kinase has been implicated as an important regulator of inflammatory responses mediated by cytokines and chemokines. Because proinflammatory cytokines play a critical role in left ventricular (LV) remodeling after myocardial infarction (MI), we examined whether long-term blockade of Rho-kinase suppresses LV remodeling in a mouse model of MI in vivo. Methods and Results-Mice underwent ligation of the left coronary artery and were treated with a Rho-kinase inhibitor, fasudil (100 mg · kg Ϫ1 · d Ϫ1 in tap water), for 4 weeks, starting 1 day after the surgery. At 4 weeks, LV infarct size was histologically comparable between the 2 groups. LV cavity dilatation and dysfunction evaluated by echocardiography were significantly suppressed in the fasudil group (PϽ0.05, nϭ15 to 28). The beneficial effects of fasudil were accompanied by suppression of cardiomyocyte hypertrophy and interstitial fibrosis (both PϽ0.01, nϭ6). The expression of inflammatory cytokines, including transforming growth factor (TGF)-␤ 2 , TGF-␤ 3 , and macrophage migration inhibitory factor, was upregulated in the noninfarcted LV in the control group and was significantly suppressed in the fasudil group (both PϽ0.05, nϭ10 to 11). Rho-kinase activity as evaluated by the extent of phosphorylation of the ERM family, a substrate of Rho-kinase, was significantly increased in the noninfarcted LV in the control group and was significantly suppressed in the fasudil group (PϽ0.05, nϭ5). Conclusions-These results indicate that Rho-kinase is substantially involved in the pathogenesis of LV remodeling after MI associated with upregulation of proinflammatory cytokines, suggesting a therapeutic importance of the molecule for the prevention of post-MI heart failure.

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Section: Possible Mechanisms Of the Inhibitory Effects Of Fasudil On supporting

confidence: 79%

Long-Term Inhibition of Rho-Kinase Suppresses Left Ventricular Remodeling After Myocardial Infarction in Mice

et al. 2004

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“…Y27632 treatment significantly increases the neointimal TUNEL-positive smooth muscle cells at 7 and 14 day after vascular injury [120], and this increased apoptosis is associated with significantly up-regulation of the proapoptotic Bax, suggesting that ROCK inhibition induces neointimal smooth muscle cell apoptosis through Bax up-regulation [121]. Consistent with this finding, the inhibition of ROCK with fasudil enhances smooth muscle cell apoptosis in the neointima after stent implantation in the porcine coronary artery, and this increased apoptosis is associated with down-regulation of the anti-apoptotic protein Bcl-2 [84]. Moreover, inhibition of ROCK with fasudil significantly enhances smooth muscle cell apoptosis in autologous vein grafts in rabbits [40] and in pulmonary hypertension in rats [1], further supporting a pro-survival role of ROCK in smooth muscle cells.…”

Section: In Vivo Evidencementioning

confidence: 55%

“…Moreover, inhibition of ROCK with fasudil significantly enhances smooth muscle cell apoptosis in autologous vein grafts in rabbits [40] and in pulmonary hypertension in rats [1], further supporting a pro-survival role of ROCK in smooth muscle cells. Increased smooth muscle cell apoptosis along with inhibition of smooth muscle cell proliferation, inflammatory cell infiltration and/or extracellular matrix protein production contribute to the inhibition of neointima formation via ROCK inhibition [40,84,120]. Therefore, these studies suggest that ROCK plays a pro-survival role in neointimal smooth muscle cells.…”

Section: In Vivo Evidencementioning

confidence: 83%

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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“…ROCK inhibition reduces macrophage accumulation and collagen deposition, and enhances apoptosis [71]. Treatment of porcine coronary artery with monocyte chemoattractant protein (MCP)-1 and oxidized low-density lipoprotein (LDL) or interleukin-1β leads to increased ROCK activity, intimal thickening, constrictive remodeling and accumulation of macrophages in the adventitia.…”

Section: Rock In Vascular Remodeling and Atherosclerosismentioning

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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Long-Term Inhibition of Rho-Kinase Suppresses Neointimal Formation After Stent Implantation in Porcine Coronary Arteries: Involvement of Multiple Mechanisms

Cited by 101 publications

References 54 publications

Long-Term Inhibition of Rho-Kinase Suppresses Left Ventricular Remodeling After Myocardial Infarction in Mice

Long-Term Inhibition of Rho-Kinase Suppresses Left Ventricular Remodeling After Myocardial Infarction in Mice

Rho kinase in the regulation of cell death and survival

ROCKs as therapeutic targets in cardiovascular diseases

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