Inhibition of Rho Kinase (ROCK) Leads to Increased Cerebral Blood Flow and Stroke Protection

Rikitake, Yoshiyuki; Kim, Hyung-Hwan; Huang, Zhihong; Seto, Minoru; Yano, Kazuo; Asano, Toshio; Moskowitz, Michael A.; Liao, James K.

doi:10.1161/01.str.0000181077.84981.11

Cited by 336 publications

(314 citation statements)

References 38 publications

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“…Regardless of the underlying mechanism, neuroprotective effects of ROCK inhibitors from various neuronal injuries have been reported. 38,39 In the present study, ROCK inhibitor downregulated cyclin D1, CDK4 and LIMK2 expression induced by SE via enhanced p27 Kip1 expression. Furthermore, elevated p27 Kip1 expression by DOX prevented SE-induced neuronal death.…”

Section: Discussionsupporting

confidence: 52%

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

et al. 2014

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Although the aberrant activation of cell cycle proteins has a critical role in neuronal death, effectors or mediators of cyclin D1/ cyclin-dependent kinase 4 (CDK4)-mediated death signal are still unknown. Here, we describe a previously unsuspected role of LIM kinase 2 (LIMK2) in programmed necrotic neuronal death. Downregulation of p27 Kip1 expression by Rho kinase (ROCK) activation induced cyclin D1/CDK4 expression levels in neurons vulnerable to status epilepticus (SE). Cyclin D1/CDK4 complex subsequently increased LIMK2 expression independent of caspase-3 and receptor interacting protein kinase 1 activity. In turn, upregulated LIMK2 impaired dynamic-related protein-1 (DRP1)-mediated mitochondrial fission without alterations in cofilin phosphorylation/expression and finally resulted in necrotic neuronal death. Inhibition of LIMK2 expression and rescue of DRP1 function attenuated this programmed necrotic neuronal death induced by SE. Therefore, we suggest that the ROCK-p27 Kip1 -cyclin D1/CDK4-LIMK2-DRP1-mediated programmed necrosis may be new therapeutic targets for neuronal death. The cell cycle is essential for a vital process, including proliferation, differentiation and survival of various cells. Cell cycle progression is regulated by two classes of proteins, the cyclins and the cyclin-dependent kinases (CDKs). Among them, cyclin D1 forms a complex with CDK4 and inactivates retinoblastoma protein (Rb) through phosphorylation resulting in activating E2 promoter-binding factor (E2F) family of transcription factors. Active E2F induces various gene transcriptions involving the cell cycle. 1 In post-mitotic neurons, some pathological conditions upregulate cyclin D1/CDK4 complex expression to induce activation of E2F members that contributes to increased transcription of proapoptotic molecules. 2,3 However, it is unclear whether cyclin D1 expression directly induces neuronal death for a number of following reasons. First, due to a time lag between cyclin D1/CDK4 expression and the onset of DNA fragmentation, most cyclin D1-positive neurons show TUNEL negativity. 4,5 Second, cyclin D1 level is unaltered in cultured embryonic neurons following apoptosis induction. 6 Third, Rb phosphorylation is rarely observed in vivo, 4 although cyclin D1/CDK4 complex phosphorylates Rb protein in apoptotic cultured neurons. 6 Fourth, cyclin D1 induction following ischemia is associated with regeneration and resistance to apoptosis rather than a mediator of apoptosis. 5,7,8 Fifth, effectors or mediators of cyclin D1/CDK4-mediated death signal are still unknown. Finally, neuronal death induced by various insults is morphologically necrotic rather than apoptotic. 9-12 Therefore, it is likely that some essential factors are missing in the cyclin D/CDK4-mediated neuronal death pathway.LIM kinases (LIMK1 and LIMK2) phosphorylate cofilin that is a stimulus-responsive mediator of actin dynamics. [13][14][15] Interestingly, non-phosphorylated cofilin targets mitochondrial membranes in response to apoptotic stimuli for cytochrome c releas...

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Section: Discussionsupporting

confidence: 52%

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

et al. 2014

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“…They are non-isoform-selective ROCK inhibitors that target their ATP-dependent kinase domains and are therefore equipotent in terms of inhibiting both ROCK1 and ROCK2. Furthermore, at higher concentrations, these ROCK inhibitors could also inhibit other serinethreonine kinases, such as PKA and PKC [33] . Nevertheless, compared with the other kinases, fasudil and its active metabolite, hydroxyfasudil, are relatively more selective for ROCKs, with hydroxyfasudil being slightly more selective than fasudil and Y-27632 [33] .…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, at higher concentrations, these ROCK inhibitors could also inhibit other serinethreonine kinases, such as PKA and PKC [33] . Nevertheless, compared with the other kinases, fasudil and its active metabolite, hydroxyfasudil, are relatively more selective for ROCKs, with hydroxyfasudil being slightly more selective than fasudil and Y-27632 [33] . Fasudil is the only ROCK inhibitor practically available for long-term use in vivo.…”

Section: Discussionmentioning

confidence: 99%

Involvement of RhoA/ROCK in myocardial fibrosis in a rat model of type 2 diabetes

Zhou

Wang

et al. 2011

Acta Pharmacol Sin

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Aim: To investigate whether activation of RhoA/Rho kinase (ROCK) is involved in myocardial fibrosis in diabetic hearts. Methods: A rat model of type 2 diabetes was established using high fat diet combined with streptozotocin (30 mg/kg, ip). Animals were randomly divided into 3 groups: control rats, untreated diabetic rats that received vehicle and treated diabetic rats that received Rhokinase inhibitor fasudil hydrochloride hydrate (10 mg·kg -1 ·d -1 , ip, for 14 weeks). Cardiac contractile function was evaluated in vivo. The morphological features of cardiac fibrosis were observed using immunohistochemistry and TEM. The mRNA expression of JNK, TGFβ1, type-I, and type-III procollagen was assessed with RT-PCR. The phosphorylation of MYPT1, JNK and Smad2/3, as well as the protein levels of TGFβ1 and c-Jun, were evaluated using Western blotting. Results: In untreated diabetic rats, myocardial fibrosis was developed and the heart contractility was significantly reduced as compared to the control rats. In the hearts of untreated diabetic rats, the mRNA expression level and activity of JNK were upregulated; the expression of TGFβ1 and phosphorylation of Smad2/3 were increased. In the hearts of treated diabetic rat, activation of JNK and TGFβ/Smad was significantly decreased, myocardial fibrosis was reduced, and cardiac contractile function improved. Conclusion: The data suggest that fasudil hydrochloride hydrate ameliorates myocardial fibrosis in rats with type 2 diabetes at least in part through inhibiting the JNK and TGFβ/Smad pathways. Inhibition of RhoA/ROCK may be a novel therapeutic target for prevention of diabetic cardiomyopathy.

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“…97,98 Indeed, the RhoA/ROCK pathway has been shown to be involved in the formation of atherosclerotic lesions, vasoconstriction and myocardial hypertrophy and to be activated in patients with hypertension and in patients with coronary artery disease. [99][100][101][102][103][104] Recently, we have shown that FMD is an independent predictor of leukocyte ROCK activity in healthy men and men with cardiovascular risk factors but without established cardiovascular or cerebrovascular diseases, suggesting that cumulative cardiovascular risk, including aging and hypertension, may enhance ROCK activity and endothelial dysfunction. 105 Activation of the RhoA/ROCK pathway impairs NO bioavailability through inhibition of eNOS mRNA stability, eNOS posphorylation at Ser 1177 and the Akt/PI3K pathway and enhancement of eNOS phosphorylation at Thr495.…”

Section: Tetrahydrobiopterin (Bh 4 )mentioning

confidence: 99%

Endothelial dysfunction and hypertension in aging

2012

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Hypertension is one of the common diseases in the elderly. The prevalence of hypertension markedly increases with advancing age. Both aging and hypertension have a critical role in cardiovascular and cerebrovascular complications. Although aging and hypertension, either independently or collectively, impair endothelial function, aging and hypertension may have similar cascades for the pathogenesis and development of endothelial dysfunction. Nitric oxide (NO) has an important role in regulation of vascular tone. Decrease in NO bioavailability by endothelial dysfunction would lead to elevation of blood pressure. An imbalance of reduced production of NO or increased production of reactive oxygen species, mainly superoxide, may promote endothelial dysfunction. One possible mechanism by which the prevalence of hypertension is increased in relation to aging may be advancing endothelial dysfunction associated with aging through an increase in oxidative stress. In addition, endothelial cell senescence is also involved in aging-related endothelial dysfunction. In this review, we focus on recent findings and interactions between endothelial function, oxidative stress and hypertension in aging.

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Inhibition of Rho Kinase (ROCK) Leads to Increased Cerebral Blood Flow and Stroke Protection

Cited by 336 publications

References 38 publications

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

Involvement of RhoA/ROCK in myocardial fibrosis in a rat model of type 2 diabetes

Endothelial dysfunction and hypertension in aging

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