Inhibition of Myosin Phosphatase by Upregulated Rho-Kinase Plays a Key Role for Coronary Artery Spasm in a Porcine Model With Interleukin-1β

Kimura, Tadashi; Shimokawa, Hiroaki; Miyata, Kenji; Kunihiro, Ikuko; Kawano, Yoji; Fukata, Yuko; Higo, Taiki; Egashira, Kensuke; Takahashi, Shosuke; Kaibuchi, Kozo; Takeshita, Akira

doi:10.1161/01.cir.101.11.1319

Cited by 252 publications

(219 citation statements)

References 44 publications

Supporting

Mentioning

209

Contrasting

Unclassified

Order By: Relevance

“…Both acetylcholine and 5-HT activate ROCK, and ROCK inhibitors have been demonstrated to attenuate agonist-induced coronary vasospasm [56]. ROCK inhibitors also suppress vasospasms in porcine coronary artery induced by chronic treatment with the proinflammatory mediator, inter-leukin-1β [57,58]. Indeed, elevated ROCK expression and activity are observed in vasospastic segment [58].…”

Section: Rock In Acute Coronary Syndromesmentioning

confidence: 99%

“…ROCK inhibitors also suppress vasospasms in porcine coronary artery induced by chronic treatment with the proinflammatory mediator, inter-leukin-1β [57,58]. Indeed, elevated ROCK expression and activity are observed in vasospastic segment [58]. Clinically, intracoronary administration of a ROCK inhibitor is effective in preventing coronary artery spasm and myocardial ischemia in patients with vasospastic and microvascular angina, as well as intractable severe coronary spasm following coronary artery bypass grafting [59][60][61].…”

Section: Rock In Acute Coronary Syndromesmentioning

confidence: 99%

See 1 more Smart Citation

ROCKs as therapeutic targets in cardiovascular diseases

Rikitake

Liao

2005

Expert Review of Cardiovascular Therapy

View full text Add to dashboard Cite

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

show abstract

Section: Rock In Acute Coronary Syndromesmentioning

confidence: 99%

Section: Rock In Acute Coronary Syndromesmentioning

confidence: 99%

ROCKs as therapeutic targets in cardiovascular diseases

Rikitake

Liao

2005

Expert Review of Cardiovascular Therapy

View full text Add to dashboard Cite

show abstract

“…12,14,18 Serotonin (0.1, 0.3, and 1.0 mol/L) induced contractions of the isolated coronary rings without endothelium, which rapidly developed and reached a maximum in 5 to 8 minutes. The developed tension was expressed as a percentage of that attained in the last precontraction with 62 mmol/L KCl.…”

Section: Organ Chamber Experimentsmentioning

confidence: 99%

“…We have recently demonstrated that Rho-kinase is functionally upregulated at the inflammatory coronary lesions and plays an important role in the pathogenesis of coronary hyperconstriction in our porcine model with interleukin (IL)-1␤. 12 The IL-1␤-treated coronary segment is characterized by luminal reduction caused by neointimal formation and constrictive remodeling. 13 Thus, our porcine model may be useful in the examination of the molecular mechanism of coronary arteriosclerosis in humans.…”

mentioning

confidence: 99%

Adenovirus-Mediated Transfer of Dominant-Negative Rho-Kinase Induces a Regression of Coronary Arteriosclerosis in Pigs In Vivo

Morishige

Shimokawa

Eto

et al. 2001

ATVB

Self Cite

View full text Add to dashboard Cite

Abstract-Small GTPase Rho and its target Rho-kinase/ROK/ROCK play an important role in various cellular functions, including smooth muscle contraction, actin cytoskeleton organization, and cell adhesion and migration, all of which may be involved in the pathogenesis of arteriosclerosis. Here, we show that adenovirus-mediated transfer of dominantnegative Rho-kinase (DNRhoK) induces a marked regression of coronary constrictive remodeling and abolishes coronary vasospastic activity in vivo. Porcine coronary segments were chronically treated with interleukin-1␤, which resulted in the development of constrictive remodeling and vasospastic responses to serotonin, as previously reported. Adenovirus-mediated transfer of DNRhoK, but not that of ␤-galactosidase, into the interleukin-1␤-treated coronary segment caused a marked regression of the constrictive remodeling and abolished the vasospastic activity in 3 weeks. Western blot analysis showed that the phosphorylation of adducin and the ezrin/radixin/moesin family, the target proteins of Rho-kinase, were upregulated at the coronary lesions and were significantly suppressed by the transfer of DNRhoK. Recent studies in vitro have suggested that the small GTP-binding protein Rho and its target protein Rho-kinase/ ROK/ROCK 2-4 play an important role in various cellular functions, including smooth muscle contraction, 5,6 actin cytoskeleton organization, 7,8 cell adhesion and motility, 9 cytokinesis, 10 and gene expression, 11 all of which may be involved in the pathogenesis of arteriosclerosis. We have recently demonstrated that Rho-kinase is functionally upregulated at the inflammatory coronary lesions and plays an important role in the pathogenesis of coronary hyperconstriction in our porcine model with interleukin (IL)-1␤. 12 The IL-1␤-treated coronary segment is characterized by luminal reduction caused by neointimal formation and constrictive remodeling. 13 Thus, our porcine model may be useful in the examination of the molecular mechanism of coronary arteriosclerosis in humans.We have recently found that hydroxyfasudil, an active metabolite of fasudil after oral absorption, is a potent and specific inhibitor of Rho-kinase and markedly inhibits coronary hyperconstriction and macrophage migration. 14,15 Thus, it is conceivable that Rho-kinase is involved not only in the pathogenesis of coronary artery spasm but also in that of coronary arteriosclerosis.To test this hypothesis, we examined in the present study whether selective inhibition of Rho-kinase by the local adenovirus-mediated transfer of dominant-negative Rhokinase (DNRhoK) can effectively induce a regression of coronary arteriosclerotic lesions in our porcine model in vivo. MethodsThis experiment was reviewed by the Committee of the Ethics on Animal Experiments at Kyushu University and was carried out under the control of the Guidelines for Animal Experiments at Kyushu University. Animal PreparationDomestic male pigs (2 to 3 months old, weighing 25 to 30 kg) were sedated with intramuscular ketamine hydrochloride...

show abstract

“…For example, RhoA activity is higher in aortic smooth muscle cells derived from the strokeprone spontaneously hypertensive rat than from the wild-type rat, although the expression levels of RhoA are not different between mutant and wild-type rats (20). Rho-kinase activity is up-regulated, and phosphorylation levels of MYPT1 are increased in the coronary spastic lesion in a porcine swine model (21). Subarachnoid hemorrhage induces sustained Rhokinase activation in the canine basilar artery and subsequent cerebral vasospasm (22).…”

mentioning

confidence: 98%

Rho-kinase Contributes to Sustained RhoA Activation through Phosphorylation of p190A RhoGAP

Mori

Amano

Takefuji

et al. 2009

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Inhibition of Myosin Phosphatase by Upregulated Rho-Kinase Plays a Key Role for Coronary Artery Spasm in a Porcine Model With Interleukin-1β

Abstract: These results indicate that Rho-kinase is upregulated at the spastic site and plays a key role in inducing vascular smooth muscle hypercontraction by inhibiting myosin phosphatase through the phosphorylation of MBS in our porcine model.

Cited by 252 publications

References 44 publications

ROCKs as therapeutic targets in cardiovascular diseases

ROCKs as therapeutic targets in cardiovascular diseases

Adenovirus-Mediated Transfer of Dominant-Negative Rho-Kinase Induces a Regression of Coronary Arteriosclerosis in Pigs In Vivo

Rho-kinase Contributes to Sustained RhoA Activation through Phosphorylation of p190A RhoGAP

Contact Info

Product

Resources

About