Antiischemic Properties of Fasudil in Experimental Models of Vasospastic Angina

Satoh, Shin’ichi; Ikegaki, Ichiro; Asano, Toshio; Shimokawa, Hiroaki

doi:10.1254/jjp.87.34

Cited by 30 publications

(18 citation statements)

References 21 publications

(16 reference statements)

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“…In agreement with our findings, inhibition of the Rho/ROK pathway blunted ET-1-induced vasoconstriction in mammary, mesenteric, penile, cerebral, and coronary arteries (8,(35)(36)(37)(38). Preventing coronary artery vasospasm in response to ET-1, ROK inhibition protected against myocardial ischemia in rabbits (13,39).…”

Section: Discussionsupporting

confidence: 91%

“…A recently developed ROK inhibitor, the pyridine derivative Y-27632, has been shown to potently inhibit the contraction of preparations from experimental animals and human arterial vessels induced by different agonists in vitro and also to correct arterial pressure to normotensive levels in different experimental models of hypertension in vivo (8 -11). Because of the evidence that the Rho/ROK pathway mediates tonic vasoconstriction, ROK is thought to play a crucial role in human diseases, e.g., in hypertension and myocardial ischemia (12,13). The contribution of the ROK pathway to renal vasoconstriction is practically unknown.…”

mentioning

confidence: 99%

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Rho-Kinase Inhibition Blunts Renal Vasoconstriction Induced by Distinct Signaling Pathways In Vivo

Cavarape

Endlich²,

Assaloni³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. In addition to intracellular calcium, which activates myosin light chain (MLC) kinase, MLC phosphorylation and hence contraction is importantly regulated by MLC phosphatase (MLCP). Recent evidence suggests that distinct signaling cascades of vasoactive hormones interact with the Rho/Rho kinase (ROK) pathway, affecting the activity of MLCP. The present study measured the impact of ROK inhibition on vascular F-actin distribution and on vasoconstriction induced by activation/inhibition of distinct signaling pathways in vivo in the microcirculation of the split hydronephrotic rat kidney.

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

Rho-Kinase Inhibition Blunts Renal Vasoconstriction Induced by Distinct Signaling Pathways In Vivo

Cavarape

Endlich²,

Assaloni³

et al. 2003

Journal of the American Society of Nephrology

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“…We demonstrated that pretreatment with fasudil before reperfusion prevents endothelial dysfunction and reduces the extent of myocardial infarction in dogs in vivo. 213 The beneficial effect of fasudil has also been demonstrated in a rabbit model of myocardial ischemia induced by intravenous administration of endothelin-1, 214 a canine model of pacing-induced myocardial ischemia, 215 and a rat model of vasopressin-induced chronic myocardial ischemia. January 22, 2016…”

Section: Rho-kinase In Cardiac Hypertrophy and Failurementioning

confidence: 98%

RhoA/Rho-Kinase in the Cardiovascular System

Shimokawa

Sunamura

Satoh

2016

Circulation Research

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352

235

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Twenty years ago, Rho-kinase was identified as an important downstream effector of the small GTP-binding protein, RhoA. Thereafter, a series of studies demonstrated the important roles of Rho-kinase in the cardiovascular system. The RhoA/Rho-kinase pathway is now widely known to play important roles in many cellular functions, including contraction, motility, proliferation, and apoptosis, and its excessive activity induces oxidative stress and promotes the development of cardiovascular diseases. Furthermore, the important role of Rho-kinase has been demonstrated in the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, and heart failure. Cyclophilin A is secreted by vascular smooth muscle cells and inflammatory cells and activated platelets in a Rho-kinase–dependent manner, playing important roles in a wide range of cardiovascular diseases. Thus, the RhoA/Rho-kinase pathway plays crucial roles under both physiological and pathological conditions and is an important therapeutic target in cardiovascular medicine. Recently, functional differences between ROCK1 and ROCK2 have been reported in vitro. ROCK1 is specifically cleaved by caspase-3, whereas granzyme B cleaves ROCK2. However, limited information is available on the functional differences and interactions between ROCK1 and ROCK2 in the cardiovascular system in vivo. Herein, we will review the recent advances about the importance of RhoA/Rho-kinase in the cardiovascular system.

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“…We have demonstrated that pretreatment with fasudil before reperfusion prevents endothelial dysfunction and reduces the extent of myocardial infarction in dogs in vivo. 132 The beneficial effect of fasudil has also been demonstrated in a rabbit model of myocardial ischemia induced by intravenous administration of endothelin-1, 133 a canine model of pacing-induced myocardial ischemia, 134 and a rat model of vasopressin-induced chronic myocardial ischemia.…”

Section: Aortic Aneurysmmentioning

confidence: 98%

2015 ATVB Plenary Lecture

Shimokawa

Satoh

2015

ATVB

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Abstract-Rho-kinase (ROCKs) is an important downstream effector of the small GTP-binding protein Ras homolog gene family member A. There are 2 isoforms of ROCK, ROCK1 and ROCK2, and they have different functions in several vascular components. The Ras homolog gene family member A/ROCK pathway plays an important role in various fundamental cellular functions, including contraction, motility, proliferation, and apoptosis, whereas its excessive activity is involved in the pathogenesis of cardiovascular diseases. For the past 20 years, a series of translational research studies have demonstrated the important roles of ROCK in the pathogenesis of cardiovascular diseases. At the molecular and cellular levels, ROCK upregulates several molecules related to inflammation, thrombosis, and fibrosis. In animal experiments, ROCK plays an important role in the pathogenesis of vasospasm, arteriosclerosis, hypertension, pulmonary hypertension, and heart failure. Finally, at the human level, ROCK is substantially involved in the pathogenesis of coronary vasospasm, angina pectoris, hypertension, pulmonary hypertension, and heart failure. Furthermore, ROCK activity in circulating leukocytes is a useful biomarker for the assessment of disease severity and therapeutic responses in vasospastic angina, heart failure, and pulmonary hypertension. In addition to fasudil, many other ROCK inhibitors are currently under development for various indications. Thus, the ROCK pathway is an important novel therapeutic target in cardiovascular medicine. ). [20][21][22][23] Both endothelial NO production and NO-mediated signaling in VSMC are targets and effectors of the RhoA/ROCK pathway. 1,24,25 In EC, the RhoA/ROCK pathway negatively regulates NO production, although in VSMC, the pathway enhances MLC phosphorylation through inhibition of MYPT-1 of MLCP and promotes VSMC contraction ( Figure 1). 26ROCK is a serine/threonine kinase, which is encoded by 2 different genes. In humans, ROCK1 (ROCKβ) and ROCK2 (ROCKα) genes are located separately on chromosome 18 and 2, respectively. 27,28 ROCK consists of 3 major domains, including a kinase domain, a coiled-coil domain that include Rhobinding domain and a putative pleckstrin homology domain ( Figure 3). 4 ROCK activity is enhanced by binding of GTPbound active form of RhoA.28 Several ROCK substrates have been identified 27 and phosphorylation of ROCK-mediated substrate causes actin filament formation, organization, and cytoskeleton rearrangement (Figure 1). 29 Nowadays, many ROCK inhibitors, such as fasudil 30 and Y-27632, 31 have been developed and they inhibit ROCK activity in a competitive manner with ATP at the Rho-binding site. 32 Among them, hydroxyfasudil, a major active metabolite of fasudil, exerts a more specific inhibitory effect on ROCK. 33,34 Roles of ROCK in ECThe RhoA/ROCK pathway is critically involved in actin dynamics. 35 Cyclic strain stimulates RhoA activation and enhances cell contractility. Mechanical activation of the RhoA/ROCK system makes cells more sensitive to external stimuli...

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Antiischemic Properties of Fasudil in Experimental Models of Vasospastic Angina

Cited by 30 publications

References 21 publications

Rho-Kinase Inhibition Blunts Renal Vasoconstriction Induced by Distinct Signaling Pathways In Vivo

Rho-Kinase Inhibition Blunts Renal Vasoconstriction Induced by Distinct Signaling Pathways In Vivo

RhoA/Rho-Kinase in the Cardiovascular System

2015 ATVB Plenary Lecture

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