Contribution of Rho A and Rho Kinase to Platelet-Derived Growth Factor-BB-Induced Proliferation of Vascular Smooth Muscle Cells.

Kamiyama, Masumi; Utsunomiya, Kazunori; Taniguchi, Kanta; Yokota, Tamotsu; Kurata, Hiroyuki; Tajima, Naoko; Kondo, Kazuo

doi:10.5551/jat.10.117

Cited by 54 publications

(35 citation statements)

References 31 publications

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“…Furthermore, similar results were obtained for ERK activity that is known to be important for VSMC migration and proliferation. [33][34][35] However, we observed less dramatic changes in ROCK and ERK activities compared with those in the degree of PH, which could be explained by the fact that we used whole mouse lung tissue for Western blot that contains not only VSMC but also many other types of cells. In addition, we confirmed that pulmonary arteries from patients with IPAH revealed enhanced ERK activity.…”

Section: Discussionmentioning

confidence: 53%

Crucial Role of ROCK2 in Vascular Smooth Muscle Cells for Hypoxia-Induced Pulmonary Hypertension in Mice

Shimizu

Fukumoto

Tanaka

et al. 2013

ATVB

104

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P ulmonary arterial hypertension (PAH) is a fatal disease characterized by increased pulmonary vascular resistance, leading to right heart failure and death.1,2 Increased pulmonary vascular resistance is caused by distal pulmonary vascular remodeling, including prolonged vasoconstriction, proliferation and migration of vascular smooth muscle cells (VSMCs), and endothelial injury.3 Although multiple pharmacological agents, such as vasodilators and anticoagulants, have been developed for the treatment of PAH, long-term prognosis of patients with severe PAH remains poor because of progressive right heart failure. 3 Thus, more effective treatments need to be urgently developed.Rho-kinase (ROCK) belongs to the serine/threonine kinases family and is an important downstream effector of the small GTP-binding protein RhoA. It has been demonstrated that Rho/ROCK pathway plays an important role in various fundamental cellular functions, including contraction, motility, proliferation, and migration, leading to the development of cardiovascular diseases, including PAH. 4,5 There are 2 isoforms of ROCK: ROCK1 (Rho-kinase β) and ROCK2 (Rho-kinase α).6 ROCK1 and ROCK2 are highly homologous, sharing 65% homology in amino acid sequence and 92% homology in their kinase domains. 6 Both isoforms are ubiquitously expressed in invertebrates and vertebrates with ROCK1 expressed mainly in circulating inflammatory cells and ROCK2 in VSMC. 7,8 Homozygous ROCK1-deficient mice show open eyelids at birth and omphalocele, whereas homozygous ROCK2-deficient mice die embryonically because of placental dysfunction, 9,10 suggesting that ROCK1 and ROCK2 mediate different functions in different types of cells.We have previously reported that a long-term treatment with an isoform-nonspecific ROCK inhibitor, fasudil, suppresses the development of monocrotaline-induced and hypoxia-induced pulmonary hypertension (PH) in animal models.11,12 Furthermore, we have recently obtained a direct evidence for increased ROCK activation in patients with idiopathic PAH (IPAH). 13 However, although isoform-nonspecific ROCK inhibitors were effective in previous studies of PAH in both animals and humans, 14 the particular isoform of ROCK responsible for the effect has not been evaluated.It was previously reported that heterozygous ROCK1-deficient mice had decreased neointima formation after carotid artery ligation associated with reduced leukocytemediated inflammation. 15 Thus, ROCK1 seems to play an important role in circulating inflammatory cells in the pathogenesis of vascular diseases. 7,8 In contrast, Rho/ROCK2 pathway plays a central role in VSMC-mediated vasoconstriction © 2013 American Heart Association, Inc. Objective-Rho/Rho-kinase (ROCK) pathway in vascular smooth muscle cells (VSMCs) plays an important role in the pathogenesis of cardiovascular diseases, including pulmonary arterial hypertension (PAH). Rho-kinase has 2 isoforms, ROCK1 and ROCK2, with different functions in different cells; ROCK1 for circulating inflammatory cells and ROCK2 for the vas...

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Section: Discussionmentioning

confidence: 53%

Crucial Role of ROCK2 in Vascular Smooth Muscle Cells for Hypoxia-Induced Pulmonary Hypertension in Mice

Shimizu

Fukumoto

Tanaka

et al. 2013

ATVB

104

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“…4). Therefore, our result shows that the change of Rho-kinase activation does not appear in the early stages of atherosclerosis, although involvement of the kinase in the disease has been reported previously 20,[37][38][39][40] ; however, we are not able to reject the alterations of other contractionrelated signal pathways in the early stage of the syndrome. The decrease in PE-induced maximal contraction in apoE-KO mouse aorta suggests that the Rho/ Rho-kinase-independent signal pathway is impaired in the early stage of atherosclerosis.…”

Section: Discussioncontrasting

confidence: 36%

Role of Rho/Rho-Kinase and NO/cGMP Signaling Pathways in Vascular Function Prior to Atherosclerosis

Mori-Kawabe

Tsushima

Fujimoto

et al. 2009

JAT

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Aim: Atherosclerosis is a cardiovascular disease; however, there is little information on signal transduction for vascular function in the early stage of atherosclerosis. In this work, we investigated the role of Rho/Rho-kinase and nitrogen oxide (NO)/cyclic GMP (cGMP) signaling pathways in the aorta prior to atherosclerosis. Methods: Tension, the expression of RhoA protein, Rho-kinase activity and the cGMP level were measured using endothelium-intact or -denuded aorta prepared from apolipoprotein E-deficient (apoE-KO) and C57BL/6 wild-type (WT) mice at 2 months of age. Results: Phenylephrine (PE) induced less maximal contraction in the endothelium-denuded aorta from apoE-KO than from WT mice. A Rho-kinase inhibitor (Y-27632) reduced more effectively the contraction of apoE-KO than WT mice, but their RhoA proteins and Rho-kinase activities were not so different. Acetylcholine caused larger relaxation of the PE-stimulated, endothelium-intact aorta in apoE-KO due to endothelial NO release than WT mice. The basal cGMP level in the endotheliumintact aorta of apoE-KO mice was higher than that of WT. Conclusions: Smooth muscle contraction via 1-adrenergic receptor shows higher dependency on Rho-kinase activity, suggesting down-regulation of the mechanism different from Rho/Rho kinase signaling in the aorta prior to atherosclerosis. Endothelium-dependent relaxation is also intensified through the NO/cGMP pathway.

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“…p38 MAPK is also reportedly involved in Rho-kinase-mediated epithelial-mesenchymal transition (35), production of profibrotic mediators (41), and neuronal degeneration (49). Moreover, ERK, another member of the MAPK family, has been implicated in Rho/Rho-kinase-induced proliferation of vascular smooth muscle cells (16). These findings indicate that MAPKs are important mediators of the Rho/Rhokinase pathway and that individual MAPKs make distinct contributions to Rho/Rho-kinase signaling in a variety of contexts.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of the Rho/Rho-kinase pathway leads to the phosphorylation of downstream substrates, including myosin phosphatase target subunit (19), which has been postulated to control a variety of cellular functions such as cell proliferation, contraction, migration, and transcriptional regulation (8). A series of recent animal model studies have implicated Rho/Rho-kinase signaling in cardiovascular (16,44) and renal (34,36) disease. Furthermore, studies from our own laboratory and others have shown that pharmacological inhibition of Rho-kinase in experimental models of diabetes results in a significant reduction in albuminuria, accumulation of glomerular matrix (29), and infiltration of macrophages (18).…”

mentioning

confidence: 99%

Rho-kinase regulation of TNF-α-induced nuclear translocation of NF-κB RelA/p65 and M-CSF expression via p38 MAPK in mesangial cells

Matoba

Kawanami

Tsukamoto

et al. 2014

American Journal of Physiology-Renal Physiology

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The small GTPase Rho and its downstream effector, Rho-associated coiled-coil containing protein kinase (Rho-kinase), regulate a number of cellular processes, including organization of the actin cytoskeleton, cell adhesion, and migration. While pharmacological inhibitors of Rhokinase signaling are known to block renal inflammation, the molecular basis for this effect is unclear. Here, we provide evidence that proinflammatory TNF-␣ promotes mesangial expression of macrophage colony-stimulating factor (M-CSF), a key regulator for the growth and differentiation of mononuclear phagocytes, in a Rhokinase-dependent manner. Consistent with this observation, TNF-␣-mediated renal expression of M-CSF in insulin-resistant db/db mice was downregulated by Rho-kinase inhibition. Small interfering RNAfacilitated knockdown of Rho-kinase isoforms ROCK1 and ROCK2 indicated that both isoforms make comparable contributions to regulation of M-CSF expression in mesangial cells. From a mechanistic standpoint, Western blotting and EMSA showed that Rho-kinase and its downstream target p38 MAPK regulate nuclear translocation of NF-B RelA/p65 and subsequent DNA binding activity, with no significant effects on IB␣ degradation and RelA/p65 phosphorylation. Moreover, we showed that Rho-kinase-mediated cytoskeletal organization is required for the nuclear uptake of RelA/p65. Collectively, these findings identify Rho-kinase as a critical regulator of chemokine expression and macrophage proliferation.

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Contribution of Rho A and Rho Kinase to Platelet-Derived Growth Factor-BB-Induced Proliferation of Vascular Smooth Muscle Cells.

Cited by 54 publications

References 31 publications

Crucial Role of ROCK2 in Vascular Smooth Muscle Cells for Hypoxia-Induced Pulmonary Hypertension in Mice

Crucial Role of ROCK2 in Vascular Smooth Muscle Cells for Hypoxia-Induced Pulmonary Hypertension in Mice

Role of Rho/Rho-Kinase and NO/cGMP Signaling Pathways in Vascular Function Prior to Atherosclerosis

Rho-kinase regulation of TNF-α-induced nuclear translocation of NF-κB RelA/p65 and M-CSF expression via p38 MAPK in mesangial cells

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