Fasudil hydrochloride hydrate, a Rho‐kinase inhibitor, suppresses isoproterenol‐induced heart failure in rats via JNK and ERK1/2 pathways

Wang, Na; Guan, Peng; Zhang, Jianping; Li, Yaqing; Chang, Yan‐Zhong; Shi, Zhenhua; Wang, Fengyun; Chu, Li

doi:10.1002/jcb.23112

Cited by 48 publications

(36 citation statements)

References 41 publications

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“…This seems to be because of a side-effect of the inhibitor in the epidermis, namely the concomitant inhibition of Rok signaling and ERK phosphorylation ( Supplementary Fig. S8B), sporadically observed in other tissues (25)(26)(27). ERK inhibition by Fasudil is not observed in the forestomach (Fig.…”

Section: A B Cmentioning

confidence: 95%

Skin Tumorigenesis Stimulated by Raf Inhibitors Relies Upon Raf Functions That Are Dependent and Independent of ERK

et al. 2013

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RAF inhibitors achieve unprecedented but mainly transient clinical responses in patients with melanoma whose tumors harbor an activating BRAF mutation. One notable side-effect of RAF inhibitors is the stimulation of cutaneous skin tumors, arising in about 30% of patients receiving these drugs, which are thought to develop as a result of inhibitor-induced activation of wild-type Raf in occult precursor skin lesions. This effect raises the possibility that less manageable tumors might also arise in other epithelial tissues. Here we provide preclinical evidence supporting this disquieting hypothesis by showing that the RAF inhibitors PLX-4032 (vemurafenib) and GDC-0879 precipitate the development of cell-autonomous, Ras-driven tumors in skin and gastric epithelia. The magnitude of the effects correlated with the inhibitors' relative abilities to induce ERK activation. Epidermisrestricted ablation of either B-Raf or C-Raf prevented PLX-4032-induced ERK activation and tumorigenesis. In contrast, GDC-0879 induced ERK activation and tumorigenesis in B-Raf-deficient epidermis, whereas C-Raf ablation blocked GDC-0879-induced tumorigenesis (despite strong ERK activation) by preventing Rokamediated keratinocyte dedifferentiation. Thus, inhibitor-induced ERK activation did not require a specific Raf kinase. ERK activation was necessary, but not sufficient for Ras þ Raf inhibitor-induced tumorigenesis, whereas C-Raf downregulation of Roka was essential even in the face of sustained ERK signaling to prevent differentiation and promote tumorigenesis. Taken together, our findings suggest that combination therapies targeting ERKdependent and -independent functions of Raf may be more efficient but also safer for cancer treatment. Cancer Res; 73(23); 6926-37. Ó2013 AACR.

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Section: A B Cmentioning

confidence: 95%

Skin Tumorigenesis Stimulated by Raf Inhibitors Relies Upon Raf Functions That Are Dependent and Independent of ERK

et al. 2013

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“…Recently, it has been demonstrated that the nuclear translocation of phosphorylated ERK1/2 depends on the Rho-kinase activity. 58 Fasudil inhibits VSMC proliferation by blocking the nuclear translocation of ERK1/2. 59 All of these reports support our present study finding that treatment with fasudil inhibited the phosphorylation of Rho-kinase and ERK1/2.…”

Section: Additive and Synergistic Effects Of The Combination Therapymentioning

confidence: 99%

Combination Therapy With Fasudil and Sildenafil Ameliorates Monocrotaline-Induced Pulmonary Hypertension and Survival in Rats

Elias-Al-Mamun

Satoh

Tanaka

et al. 2014

Circ J

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“…20 However, aberrations in ERK1/2 signaling are known to occur in a wide range of pathologies, including cancer, diabetes, viral infection, and cardiovascular disease. 21,22 In preliminary studies, authors have indicated that ERK1/2 is highly abundant in both SS and normal RBCs. Yet, whether this kinase remains functional in normal or SS RBCs is unknown, and an extremely critical question in the study of SCD pathophysiology.…”

mentioning

confidence: 99%

Erythrocyte plasma membrane–bound ERK1/2 activation promotes ICAM-4–mediated sickle red cell adhesion to endothelium

Zennadi¹,

Whalen

Soderblom

et al. 2012

Blood

114

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IntroductionSickle (homozygous hemoglobin S, SS) RBC-based adhesion and vaso-occlusive events likely initiate and/or exacerbate the profound vasculopathy present in patients with sickle cell disease (SCD). 1,2 SS RBCs possess unusually active signaling pathways that contribute to a panoply of abnormalities, including RBC adhesion to the endothelium and vaso-occlusion. [2][3][4] Cell adhesion is a multistep cellular process that is regulated by complex extracellular and intracellular signals that may differ from one cell type to another. We have previously shown that abnormal SS RBC interaction with the endothelium and with leukocytes can be induced via ␤ 2 adrenergic receptor (␤ 2 AR) activation by the stress hormone epinephrine. [4][5][6] Such stimulation activates the intracellular cAMP/protein kinase A (PKA) pathway. 4 ␤ 2 ARs are prototypic G-coupled receptors whose signaling properties are in part mediated by the activation of stimulatory GTP-binding proteins (G s proteins), which in turn activate adenylate cyclase (AC), leading to the generation of cAMP and the subsequent activation of PKA. The cAMP/PKA pathway can modulate the MAPK/ERKs cascade both directly and indirectly. 7-9 PKA has been reported to stimulate B-Raf, while inhibiting c-Raf. Therefore, the activity of downstream signaling proteins, such as MEKs and ERKs, could be either enhanced or inhibited depending on the balance of c-Raf and B-Raf activation. 10,11 The cellular functions mediated by ␤ 2 ARs can also be independent of adenylyl cyclase activation and involve other mediators instead. [12][13][14][15] The functions attributed to ERK1/2 at both the cellular and physiologic levels are diverse, including modulation of proliferation, differentiation, apoptosis, migration, and cell adhesion. [16][17][18][19] Physiologically, ERK1/2 is required for immune system development, homeostasis and antigen activation, memory formation, development of the heart, and responses to many hormones, growth factors, and insulin. Most of these previous studies have involved only nucleated cells, including erythroid cells, in which erythropoietin is the primary regulatory cytokine of this pathway. 20 However, aberrations in ERK1/2 signaling are known to occur in a wide range of pathologies, including cancer, diabetes, viral infection, and cardiovascular disease. 21,22 In preliminary studies, authors have indicated that ERK1/2 is highly abundant in both SS and normal RBCs. Yet, whether this kinase remains functional in normal or SS RBCs is unknown, and an extremely critical question in the study of SCD pathophysiology. Such a mechanism of action could represent a novel target for the treatment of SCD. Methods Endothelial cellsPrimary HUVECs were grown as monolayers in EBM2 medium (Lonza Walkersville) supplemented with EGM2 (Lonza Walkersville) as described previously. 4 All experiments were approved by the Duke University institutional review board. AntibodiesAbs used included the following monoclonal and polyclonal Abs (as purified Ig unless otherwise noted): B...

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Fasudil hydrochloride hydrate, a Rho‐kinase inhibitor, suppresses isoproterenol‐induced heart failure in rats via JNK and ERK1/2 pathways

Cited by 48 publications

References 41 publications

Skin Tumorigenesis Stimulated by Raf Inhibitors Relies Upon Raf Functions That Are Dependent and Independent of ERK

Skin Tumorigenesis Stimulated by Raf Inhibitors Relies Upon Raf Functions That Are Dependent and Independent of ERK

Combination Therapy With Fasudil and Sildenafil Ameliorates Monocrotaline-Induced Pulmonary Hypertension and Survival in Rats

Erythrocyte plasma membrane–bound ERK1/2 activation promotes ICAM-4–mediated sickle red cell adhesion to endothelium

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