Rho-Kinase Inhibitor Improves Increased Vascular Resistance and Impaired Vasodilation of the Forearm in Patients With Heart Failure

Kishi, Takuya; Hirooka, Yoshitaka; Masumoto, Akihiro; Izutsu, Koji; Kimura, Yoshikuni; Inokuchi, K; Tagawa, Tatsuya; Shimokawa, Hiroaki; Takeshita, Akira; Sunagawa, Kenji

doi:10.1161/circulationaha.104.510248

Cited by 119 publications

(68 citation statements)

References 56 publications

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“…Several small clinical studies have demonstrated that the pharmacological inhibition of rho-kinase (ROCK) using fasudil, to be beneficial as an anti-anginal agent [170], to be neuroprotective in acute ischemic stroke [171] and to improve endothelial function in heart failure patients [172]. Whether ROCK inhibitors administered at the time of myocardial reperfusion to AMI patients, are beneficial, remains to be determined.…”

Section: Activators Of the Risk Pathway Which Have Failed To Demonstrmentioning

confidence: 99%

Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection

2007

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Following an acute myocardial infarction (AMI), early coronary artery reperfusion remains the most effective means of limiting the eventual infarct size. The resultant left ventricular systolic function is a critical determinant of the patient's clinical outcome. Despite current myocardial reperfusion strategies and ancillary antithrombotic and antiplatelet therapies, the morbidity and mortality of an AMI remain significant, with the number of patients developing cardiac failure increasing, necessitating the development of novel strategies for cardioprotection which can be applied at the time of myocardial reperfusion to reduce myocardial infarct size. In this regard, the Reperfusion Injury Salvage Kinase (RISK) Pathway, the term given to a group of pro-survival protein kinases (including Akt and Erk1/2), which confer powerful cardioprotection, when activated specifically at the time of myocardial reperfusion, provides an amenable pharmacological target for cardioprotection. Preclinical studies have demonstrated that an increasing number of agents including insulin, erythropoietin, adipocytokines, adenosine, volatile anesthetics natriuretic peptides and 'statins', when administered specifically at the time of myocardial reperfusion, reduce myocardial infarct size through the activation of the RISK pathway. This recruits various survival pathways that include the inhibition of mitochondrial permeability transition pore opening. Interestingly, the RISK pathway is also recruited by the cardioprotective phenomena of ischemic preconditioning (IPC) and postconditioning (IPost), enabling the use of pharmacological agents which target the RISK pathway, to be used at the time of myocardial reperfusion, as pharmacological mimetics of IPC and IPost. This article reviews the origins and evolution of the RISK pathway, as part of a potential common cardioprotective pathway, which can be activated by an ever-expanding list of agents administered at the time of myocardial reperfusion, as well as by IPC and IPost. Preliminary clinical studies have demonstrated myocardial protection with several of these pharmacological activators of the RISK pathway in AMI patients undergoing PCI. Through the use of appropriately designed clinical trials, guided by the wealth of existing preclinical data, the administration of pharmacological agents which are known to activate the RISK pathway, when applied as adjuvant therapy to current myocardial reperfusion strategies for patients presenting with an AMI, should lead to improved clinical outcomes in this patient group.

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Section: Activators Of the Risk Pathway Which Have Failed To Demonstrmentioning

confidence: 99%

Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection

2007

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“…ROCK is a downstream mediator of RhoA and is believed to play a critical role in mediating the effects of RhoA on stress fiber formation, smooth muscle contraction, cell adhesion, membrane ruffling, and cell motility (13,14). The Rho͞ROCK pathway is an attractive candidate in the pathogenesis of heart failure, with a potential role in both ventricular remodeling and impaired peripheral vascular resistance (15,16). We asked whether endogenous ROCK-1 was cleaved in heart disease, and if so, what the functional consequences were.…”

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confidence: 99%

Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosis

Chang

Xie²,

Shah

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

204

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Rho-associated coiled-coil protein kinase 1 (ROCK-1) is a direct cleavage substrate of activated caspase-3, which is associated with heart failure. In the course of human heart failure, we found marked cleavage of ROCK-1 resulting in a 130-kDa subspecies, which was absent in normal hearts and in an equivalent cohort of patients with left ventricular assist devices. Murine cardiomyocytes treated with doxorubicin led to enhanced ROCK-1 cleavage and apoptosis, all of which was blocked by a caspase-3 inhibitor. In addition, a bitransgenic mouse model of severe cardiomyopathy, which overexpresses Gq protein and hematopoietic progenitor kinase-͞germinal center kinase-like kinase, revealed the robust accumulation of the 130-kDa ROCK-1 cleaved fragment. This constitutively active ROCK-1 subspecies, when expressed in cardiomyocytes, led to caspase-3 activation, indicating a positive feedforward regulatory loop. ROCK-1-dependent caspase-3 activation was coupled with the activation of PTEN and the subsequent inhibition of protein kinase B (Akt) activity, all of which was attenuated by siRNA directed against ROCK-1 expression. Similarly, ROCK-1-null mice (Rock-1 ؊/؊ ) showed a marked reduction in myocyte apoptosis associated with pressure overload. These data suggest an obligatory role for ROCK-1 cleavage in promoting apoptotic signals in myocardial hypertrophy and͞or failure.heart failure ͉ left ventricle assist device ͉ phosphatase and tensin homolog deleted on chromosome ten H eart failure is an eventual outcome for diverse cardiovascular disorders and the leading cause of combined morbidity and mortality in the United States and other developed industrial nations (1). Diverse signal transduction pathways, G proteins and protein kinases among them, likely contribute to heart failure, and the identification of essential control points have both fundamental and translational importance (2, 3). Recent findings suggest a role for the activation of the apoptotic cascade in heart failure, which may involve the activation of proteolytic caspase-3 and cardiomyocyte loss (1, 4). Although the level of apoptosis detected in the failing heart are variable (4-6), a low prevalence of apoptosis is sufficient to cause cardiac contractile depression (7). Accounting for the most conservative rate of cardiomyocyte death, the normal heart would lose most of its mass in a few decades, but the senile and failing heart lose myocytes in a matter of several months to a few years (8). This dilemma raised the issue of the imbalance between the continual loss of cardiomyocytes and the long interval for the chronic progression in heart failure. There are critical deficiencies in the available information regarding the relationship between apoptosis in the failing heart and depressed contractile function. Other mechanisms might contribute to heart failure besides cell loss. For example, we showed that activated caspase-3 mediated the cleavage of serum response factor (SRF). Cleaved SRF became a dominant negative factor that down-regulated SRF target ...

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“…18,19 In the clinic, fasudil, a potent Rho-kinase inhibitor, is effective for the treatment of a wide range of cardiovascular diseases, including cerebral and coronary vasospasm, angina, hypertension, pulmonary hypertension, and heart failure, with reasonable safety. [20][21][22][23] Rho-kinase is thus an important therapeutic target in cardiovascular medicine today. In the present study, we fi rst demonstrated that fasudil could inhibit VEGF-elicited bovine retinal endothelial cell (BREC) migration and proliferation, and corneal neovascularization, possibly by suppressing both extracellular signal-related kinase (ERK) 1/2 and Akt phosphorylation involved in cell survival and migration 24,25 in addition to Rho-kinase activity.…”

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confidence: 99%

Antiangiogenic properties of fasudil, a potent Rho-Kinase inhibitor

et al. 2008

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Rho-Kinase Inhibitor Improves Increased Vascular Resistance and Impaired Vasodilation of the Forearm in Patients With Heart Failure

Cited by 119 publications

References 56 publications

Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection

Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection

Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosis

Antiangiogenic properties of fasudil, a potent Rho-Kinase inhibitor

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