Administration of the Rho-Kinase Inhibitor Fasudil Before Ischemia or just After Reperfusion, but not 30 min After Reperfusion, Protects the Stunned Myocardium in Swine

Shibata, Itsuko; Use, Tadasuke; Ureshino, Hiroyuki; Cho, Sungsam; Maekawa, Takuji; Hara, Tetsuya; Sumikawa, Koji

doi:10.1007/s10557-008-6106-y

Cited by 10 publications

(16 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A deleterious role of RhoA/ROCK signaling in I/R injury has been demonstrated in several in vivo models including mouse, 214 rat, 215–217 dog 218 and swine. 219 In these models ROCK inhibition with fasudil 215–220 or Y27632 214,215,221 achieved smaller infarct size, less inflammation, attenuated apoptosis, and enhanced cardiac contractile function. The proposed cardioprotective mechanisms of ROCK inhibition include 1) activation of the PI3K/Akt/eNOS signaling pathway 215,216,218,220 and the JAK2/STAT3 signaling pathway; 220 2) reduction of endothelial-leukocyte interaction during ischemia-reperfusion injury by preserving endothelial function 222 and suppression of inflammatory responses; 214–216 3) reduction of endothelial cell shape changes and apoptosis through reducing actin cytoskeleton re-organization; 223,224 4) inhibition of myocyte apoptosis through increasing the expression of antiapoptotic Bcl-2 protein, 214 decreasing mitochondria-nuclear translocation of apoptotic-inducing factor through the inhibition of c-Jun NH2-terminal kinase, 217 and reducing endoplasmic reticulum stress through the elevation of sarco-endoplasmic reticulum Ca 2+ -ATPase (SERCA) activity; 220 5) improving energy production through increasing the levels of lactate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase, normalizing creatine kinase levels, and inhibiting ATP synthase degradation.…”

Section: Rock In Cardiovascular Diseasesmentioning

confidence: 95%

Rho Kinases in Cardiovascular Physiology and Pathophysiology

Shi

Wei

2013

Journal of Cardiovascular Pharmacology

137

View full text Add to dashboard Cite

Summary Rho kinase (ROCK) is a major downstream effector of the small GTPase RhoA. ROCK family, consisting of ROCK1 and ROCK2, plays central roles in the organization of actin cytoskeleton and is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, proliferation, and apoptosis. Due to the discovery of effective inhibitors such as fasudil and Y27632, the biological roles of ROCK have been extensively explored with particular attention on the cardiovascular system. In many preclinical models of cardiovascular diseases including vasospasm, arteriosclerosis, hypertension, pulmonary hypertension, stroke, ischemia-reperfusion injury and heart failure, ROCK inhibitors have shown a remarkable efficacy in reducing vascular smooth muscle cell hypercontraction, endothelial dysfunction, inflammatory cell recruitment, vascular remodeling, and cardiac remodeling. Moreover, fasudil has been used in the clinical trials of several cardiovascular diseases. The continuing utilization of available pharmacological inhibitors and the development of more potent or isoform-selective inhibitors in ROCK signaling research and in treating human diseases are escalating. In this review, we discuss the recent molecular, cellular, animal and clinical studies with a focus on the current understanding of ROCK signaling in cardiovascular physiology and diseases. We particularly note that emerging evidence suggests that selective targeting ROCK isoform based on the disease pathophysiology may represent a novel therapeutic approach for the disease treatment including cardiovascular diseases.

show abstract

Section: Rock In Cardiovascular Diseasesmentioning

confidence: 95%

Rho Kinases in Cardiovascular Physiology and Pathophysiology

Shi

Wei

2013

Journal of Cardiovascular Pharmacology

137

View full text Add to dashboard Cite

show abstract

“…Studies have shown that Rho-kinase (ROCK) is involved in various basic cellular biological activities, and the beneficial effects of ROCK inhibition against I/R injury by fasudil have been well demonstrated [18], [19], [20]. Therefore, in the present study using an in vivo rat heart I/R injury model we aimed to investigate whether ROCK inhibition by fasudil can attenuate the time- related increase in I/R injury through reduced ER stress activation for which PI3K/Akt and JAK2/STAT3 pathways might play differential roles, specifically whether SERCA activity is differentially modulated by these two signaling pathways during the reperfusion period.…”

Section: Introductionmentioning

confidence: 99%

Fasudil Protects the Heart against Ischemia-Reperfusion Injury by Attenuating Endoplasmic Reticulum Stress and Modulating SERCA Activity: The Differential Role for PI3K/Akt and JAK2/STAT3 Signaling Pathways

Zhu

Jiang

et al. 2012

PLoS ONE

View full text Add to dashboard Cite

Disordered calcium homeostasis can lead to endoplasmic reticulum (ER) stress. Our previous data showed that time course activation of ER stress contributes to time-related increase in ischemia-reperfusion (I/R) injury. However, it has not been tested whether PI3K/Akt and JAK2/STAT3 pathways play differential roles in reducing ER stress to protect the heart. In the present study, using fasudil which is a specific inhibitor of ROCK, we aimed to investigate whether improved SERCA expression and activity accounts for reduced ER stress by ROCK inhibition, specifically whether PI3K/Akt and JAK2/STAT3 pathways are differentially involved in modulating SERCA activity to reduce ER stress and hence I/R injury. The results showed that during the reperfusion period following 45 min of coronary ligation the infarct size (IS) increased from 3 h of reperfusion (45.4±5.57%) to 24 h reperfusion (64.21±5.43, P<0.05), which was associated with ER stress dependent apoptosis signaling activation including CHOP, Caspase-12 and JNK (P<0.05, respectively).The dynamic ER stress activation was also related to impaired SERCA activity at 24 h of reperfusion. Administration of fasudil at 10 mg/Kg significantly attenuated ROCK activation during reperfusion and resulted in an improved SERCA activity which was closely associated with decreases in temporal activation of ER stress and IS changes. Interestingly, while both PI3K/Akt and JAK2/STAT3 signaling pathways played equal role in the protection offered by ROCK inhibition at 3 h of reperfusion, the rescued SERCA expression and activity at 24 h of reperfusion by fasudil was mainly due to JAK2/STAT3 activation, in which PI3K/Akt signaling shared much less roles.

show abstract

“…Increased RhoA/ROCK activity has been reported in I/R injuries [155,156]. A deleterious role of RhoA/ROCK signaling in I/R injury has been demonstrated in several in vivo models including mouse [155], rat [147,156,157] and swine [158]. In these models ROCK inhibition with fasudil or Y27632 resulted in reduced infarct size, less inflammation, reduced apoptosis and enhanced contractile function.…”

Section: Rock In Cardiovascular Diseases Hypertensionmentioning

confidence: 99%

Rho Kinase As a Therapeutic Target in Cardiovascular Disease

Surma¹,

Wei²,

Shi³

2011

Future Cardiol.

166

138

View full text Add to dashboard Cite

Rho kinase (ROCK) belongs to the AGC (PKA/PKG/PKC) family of serine/threonine kinases and is a major downstream effector of the small GTPase RhoA. ROCK plays central roles in the organization of the actin cytoskeleton and is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, proliferation and gene expression. Two ROCK isoforms, ROCK1 a n d ROCK2, are assumed to be functionally redundant, based largely on the major common activators, the high degree of homology within the kinase domain and studies from overexpression with kinase constructs a n d chemical inhibitors (e.g., Y27632 a n d fasudil), which inhibit both ROCK1 and ROCK2. Extensive experimental a n d clinical studies support a critical role for the RhoA/ROCK pathway in the vascular bed in the pathogenesis of cardiovascular diseases, in which increased ROCK activity mediates vascular smooth muscle cell hypercontraction, endothelial dysfunction, inflammatory cell recruitment and vascular remodeling. Recent experimental studies, using ROCK inhibitors or genetic mouse models, indicate that the RhoA/ROCK pathway in myocardium contributes to cardiac remodeling induced by ischemic injury or persistent hypertrophic stress, thereby leading to cardiac decompensation and heart failure. This article, based on recent molecular, cellular and animal studies, focuses on the current understanding of ROCK signaling in cardiovascular diseases and in the pathogenesis of heart failure.

show abstract

Administration of the Rho-Kinase Inhibitor Fasudil Before Ischemia or just After Reperfusion, but not 30 min After Reperfusion, Protects the Stunned Myocardium in Swine

Cited by 10 publications

References 20 publications

Rho Kinases in Cardiovascular Physiology and Pathophysiology

Rho Kinases in Cardiovascular Physiology and Pathophysiology

Fasudil Protects the Heart against Ischemia-Reperfusion Injury by Attenuating Endoplasmic Reticulum Stress and Modulating SERCA Activity: The Differential Role for PI3K/Akt and JAK2/STAT3 Signaling Pathways

Rho Kinase As a Therapeutic Target in Cardiovascular Disease

Contact Info

Product

Resources

About