Rho-Kinase Inhibitor Y-27632 Attenuates Arsenic Trioxide Toxicity in H9c2 Cardiomyoblastoma Cells

Bessho, Marie; Aki, Toshihiko; Funakoshi, Takeshi; Unuma, Kana; Noritake, Kanako; Kato, Chizuru; Uemura, Kenichiro

doi:10.1007/s12012-013-9206-2

Cited by 17 publications

(9 citation statements)

References 41 publications

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“…In support of our findings, chondrocytes reportedly express ROCK proteins . In addition, it has been demonstrated that the ROCK‐mediated myosin hyperactivation leads to membrane blebbing and subsequent cell death during exposure to other drugs such as 1‐butanol, arsenic trioxide, and hydrogen sulfide …”

Section: Discussionsupporting

confidence: 89%

“…Rho‐associated coiled‐coil forming protein serine/threonine kinase (ROCK), one of the effectors of the small GTPase Rho, is known to be a key regulator of actomyosin contraction through myosin light chain (MLC) phosphorylation . Previous studies showed that the ROCK inhibitor, Y‐27632, inhibits blebbing and subsequent cell death caused by exposure to 1‐butanol, arsenic trioxide and hydrogen sulfide . ROCK‐mediated blebbing has not previously been reported to occur in chondrocytes.…”

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confidence: 99%

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Lidocaine induces ROCK-dependent membrane blebbing and subsequent cell death in rabbit articular chondrocytes

et al. 2015

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Local anesthetics are administered intraarticularly for pain control in orthopedic clinics and surgeries. Although previous studies have shown that local anesthetics can be toxic to chondrocytes, the underlying cellular mechanisms remain unclear. The present study investigates acute cellular responses associated with lidocaine-induced toxicity to articular chondrocytes. Rabbit articular chondrocytes were exposed to lidocaine and their morphological changes were monitored with live cell microscopy. The viability of chondrocytes was evaluated using a fluorescence based LIVE/DEAD assay. Acute treatment of chondrocytes with lidocaine (3-30 mM) induced spherical protrusions on the cell surface (so called "membrane blebbing") in a time-and concentration-dependent manner. The concentration-response relationship for the lidocaine effect was shifted leftward by elevating extracellular pH, as expected for the nonionized lidocaine being involved in the bleb formation. ROCK (Rho-kinase) inhibitors Y-27632 and fasudil completely prevented the lidocaine-induced membrane blebbing, suggesting that ROCK activation is required for bleb formation. Caspase-3 levels were unchanged by 10 mM lidocaine (p ¼ 0.325) and a caspase inhibitor z-VAD-fmk did not affect the lidocaine-induced blebbing (p ¼ 0.964). GTP-RhoA levels were significantly increased (p < 0.001), but Rho inhibitor-1 failed to suppress the membrane blebbing (p ¼ 0.875). Lidocaine (30 mM) reduced the cell viability of isolated chondrocytes (p < 0.001) and in situ chondrocytes (p < 0.001). The chondrotoxicity was attenuated by pretreatment of cells with ROCK inhibitors or a myosin-II inhibitor blebbistatin (p < 0.001). These findings suggest that lidocaine induces ROCK-dependent membrane blebbing and thereby produces a cytotoxic effect on chondrocytes.

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Section: Discussionsupporting

confidence: 89%

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confidence: 99%

Lidocaine induces ROCK-dependent membrane blebbing and subsequent cell death in rabbit articular chondrocytes

et al. 2015

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“…Caspase-3 is the most important terminal cleavage enzyme in the process of apoptosis. Caspase-3 can induce a conformational change in ROCK-1 during apoptosis, which leads to a persistent activation state of ROCK-1 ( 24 , 25 ). The results of the present study demonstrated that the expression of Rho and ROCK1 was downregulated and the phosphorylation level of MYPT-1 in the lung tissue was decreased in the group treated with fasudil.…”

Section: Discussionmentioning

confidence: 99%

Role of the Rho/ROCK signaling pathway in the protective effects of fasudil against acute lung injury in septic rats

2018

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Fasudil, which is primarily prescribed to treat cerebral vasospasm, may also inhibit systemic inflammation and prevent sepsis-induced acute lung injury (ALI) in rats, although the mechanisms remain elusive. The purpose of the present study was to investigate the role of the rhodopsin (Rho)/Rho-associated protein kinase (ROCK) signaling pathway in the protective effects of fasudil on ALI in septic rats. A total of 60 Wistar rats were pretreated with fasudil (30 mg/kg) through intraperitoneal injections 1 h prior to cecal ligation and puncture. Administration of fasudil led to reductions in polymorphonuclear neutrophil counts, and the protein concentrations of tumor necrosis factor-α, interleukin (IL)-1β and IL-6 in the bronchoalveolar lavage fluid of rats with sepsis-induced ALI. The results demonstrated that fasudil decreased sepsis-induced bacteremia. In addition, fasudil effectively reduced the Evans blue content, wet/dry lung weight ratio, lung injury score, and expression levels of malondialdehyde and myeloperoxidase. However, the superoxide dismutase activity in the lung tissue of the rats was increased. Activated caspase-3 activity in lung tissue was reduced to 29% by fasudil. Furthermore, the expression of Rho and ROCK1 was significantly downregulated, and the phosphorylation of myosin phosphatase-targeting subunit 1 in lung tissues was markedly decreased, whereas the protein expression levels of zonula occludens 1 were increased in fasudil-treated rats (P<0.05). In the in vitro experiments, vascular endothelial growth factor, intracellular adhesion molecule 1 and vascular cell adhesion molecule 1 secreted from human pulmonary microvascular endothelial cells treated with lipopolysaccharide (LPS) were attenuated by fasudil. Fasudil also reduced the fluorescence intensity of filamentous actin induced by LPS. Taken together, the results of the present study demonstrated that fasudil was able to improve endothelial permeability and inhibit inflammation, oxidative stress and cellular apoptosis in order to alleviate ALI in septic rats through inhibition of the Rho/ROCK signaling pathway.

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“…Despite its remarkable effects on certain cancer types, ATO has adverse effects, such as cardiac toxicity; thus, its clinical applications are restricted [24-26]. ATO cardiotoxicity is known to proceed by As 3+ binding to sulfhydryl groups of proteins, thereby damaging the mitochondrial respiratory chain and generating excessive ROS, eventually leading to myocardial cell apoptosis [27, 28]. In line with previous reports, we showed that ATO treatment can increase ROS production and decrease antioxidant enzyme activity in cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Salvianolic Acid A Protects H9c2 Cells from Arsenic Trioxide-Induced Injury via Inhibition of the MAPK Signaling Pathway

Zhang

Sun

Luo

et al. 2017

Cell Physiol Biochem

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Background/Aims: This study aimed to investigate whether Salvianolic acid A (Sal A) conferred cardiac protection against Arsenic trioxide (ATO)-induced cardiotoxicity in H9c2 cells by inhibiting MAPK pathways activation. Methods: H9c2 cardiac cells were exposed to 10 µM ATO for 24 h to induce cytotoxicity. The cells were pretreated with Sal A for 4 h before exposure to ATO. Cell viability was determined utilizing the MTT assay. The percentage of apoptosis was measured by a FITC-Annexin V/PI apoptosis kit for flow cytometry. Mitochondrial membrane potential (∆Ψm) was detected by JC-1. The intracellular ROS levels were measured using an Image-iT^TM LIVE Green Reactive Oxygen Species Detection Kit. The apoptosis-related proteins and the MAPK signaling pathways proteins expression were quantified by Western blotting. Results: Sal A pretreatment increased cell viability, suppressed ATO-induced mitochondrial membrane depolarization, and significantly altered the apoptotic rate by enhancing endogenous antioxidative enzyme activity and ROS generation. Signal transduction studies indicated that Sal A suppressed the ATO-induced activation of the MAPK pathway. More importantly, JNK, ERK, and p38 inhibitors mimicked the cytoprotective activity of Sal A against ATO-induced injury in H9c2 cells by increasing cell viability, up-regulating Bcl-2 protein expression, and down-regulating both Bax and caspase-3 protein expression. Conclusion: Sal A decreases the ATO-induced apoptosis and necrosis of H9c2 cells, and the underlying mechanisms of this protective effect of Sal A may be connected with the MAPK pathways.

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Rho-Kinase Inhibitor Y-27632 Attenuates Arsenic Trioxide Toxicity in H9c2 Cardiomyoblastoma Cells

Cited by 17 publications

References 41 publications

Lidocaine induces ROCK-dependent membrane blebbing and subsequent cell death in rabbit articular chondrocytes

Lidocaine induces ROCK-dependent membrane blebbing and subsequent cell death in rabbit articular chondrocytes

Role of the Rho/ROCK signaling pathway in the protective effects of fasudil against acute lung injury in septic rats

Salvianolic Acid A Protects H9c2 Cells from Arsenic Trioxide-Induced Injury via Inhibition of the MAPK Signaling Pathway

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