Rho-associated protein kinase isoforms stimulate proliferation of vascular smooth muscle cells through ERK and induction of cyclin D1 and PCNA

Zhao, Ying; Lv, Miao; Lin, Haishuang; Cui, Ying; Xin, Wei; Qin, Yuanhua; Kohama, Kazuhiro; Gao, Ying

doi:10.1016/j.bbrc.2013.02.009

Cited by 35 publications

(25 citation statements)

References 22 publications

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“…On the other hand, ROCK1 knockdown reduced the proportion of BrDU-positive cells by ~50% (from 40.2 ± 1.6% to 21.9 ± 2.2% of the total cell population). These results support an important role for ROCK1 in vascular SMC proliferation, as previously proposed [48], and suggest that ZIPK does not affect proliferation. It is important to note that, in the experiments of Fig.…”

Section: Resultssupporting

confidence: 91%

“…This is also supported by studies of cardiomyocytes showing that ROCK inhibition reduces the expression of G1/S-phase transition-dependent proteins [54]. A recent report indicated that ROCK1 knockdown decreased PDGF-BB-generated vascular SMC proliferation by inhibiting the expression of proliferating cell nuclear antigen (PCNA) and cyclin D1 [48]. Indeed, in our study ROCK1 knockdown significantly decreased cell proliferation and the expression of both CCND2 and 3 (cyclin D2 and 3; FC for CCND2 is-1.47), although cyclin D1 was unchanged.…”

Section: Discussionmentioning

confidence: 72%

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The Effects of Knockdown of Rho-Associated Kinase 1 and Zipper-Interacting Protein Kinase on Gene Expression and Function in Cultured Human Arterial Smooth Muscle Cells

et al. 2015

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Rho-associated kinase (ROCK) and zipper-interacting protein kinase (ZIPK) have been implicated in diverse physiological functions. ROCK1 phosphorylates and activates ZIPK suggesting that at least some of these physiological functions may require both enzymes. To test the hypothesis that sequential activation of ROCK1 and ZIPK is commonly involved in regulatory pathways, we utilized siRNA to knock down ROCK1 and ZIPK in cultured human arterial smooth muscle cells (SMC). Microarray analysis using a whole-transcript expression chip identified changes in gene expression induced by ROCK1 and ZIPK knockdown. ROCK1 knockdown affected the expression of 553 genes, while ZIPK knockdown affected the expression of 390 genes. A high incidence of regulation of transcription regulator genes was observed in both knockdowns. Other affected groups included transporters, kinases, peptidases, transmembrane and G protein-coupled receptors, growth factors, phosphatases and ion channels. Only 76 differentially expressed genes were common to ROCK1 and ZIPK knockdown. Ingenuity Pathway Analysis identified five pathways shared between the two knockdowns. We focused on cytokine signaling pathways since ROCK1 knockdown up-regulated 5 and down-regulated 4 cytokine genes, in contrast to ZIPK knockdown, which affected the expression of only two cytokine genes (both down-regulated). IL-6 gene expression and secretion of IL-6 protein were up-regulated by ROCK1 knockdown, whereas ZIPK knockdown reduced IL-6 mRNA expression and IL-6 protein secretion and increased ROCK1 protein expression, suggesting that ROCK1 may inhibit IL-6 secretion. IL-1β mRNA and protein levels were increased in response to ROCK1 knockdown. Differences in the effects of ROCK1 and ZIPK knockdown on cell cycle regulatory genes suggested that ROCK1 and ZIPK regulate the cell cycle by different mechanisms. ROCK1, but not ZIPK knockdown reduced the viability and inhibited proliferation of vascular SMC. We conclude that ROCK1 and ZIPK have diverse, but predominantly distinct regulatory functions in vascular SMC and that ROCK1-mediated activation of ZIPK is not involved in most of these functions.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 72%

The Effects of Knockdown of Rho-Associated Kinase 1 and Zipper-Interacting Protein Kinase on Gene Expression and Function in Cultured Human Arterial Smooth Muscle Cells

et al. 2015

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“…In particular, Erk1/2 inhibition caused a dose-dependent decrease in the absolute number of living cells along with downregulation of cyclin D1 levels in both OSCC cell lines tested. These findings corroborate previous studies that demonstrated negative regulation of cell growth and cyclin D1 levels following Erk1/2 inhibition by means of U0126 treatment (44,47,55,56).…”

Section: Discussionsupporting

confidence: 92%

Erk1/2 activation and modulation of STAT3 signaling in oral cancer

et al. 2014

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Abstract. Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway possesses confirmed oncogenic potential in oral squamous cell carcinoma (OSCC). Crosstalk with other molecular pathways contributes to STAT3 regulation in cancer. The effects of mitogen-activated protein kinases (MAPKs) and particularly extracellular signal-regulated kinase 1/2 (Erk1/2) on STAT3 signaling in OSCC have not been thoroughly investigated. The present study examined the effects of Erk1/2 modulation on STAT3 signaling and cell growth in OSCC cells. Constitutive expression levels of phosphorylated (tyrosine and serine) and total STAT3, Erk1/2 and cyclin D1 were assessed in OSCC cell lines. Erk1/2 modulation was achieved by pharmacological agents; siRNA silencing against Erk1/2 was also performed. Cell proliferation and viability were assessed. Erk1/2 inhibition with either U0126 treatment or specific siRNA silencing resulted in decreases in p-ser STAT3 and cyclin D1 levels and increases in p-tyr STAT3 in OSCC cells. Moreover, Erk1/2 inhibition resulted in a dose-dependent reduction in OSCC cell growth and viability. Erk1/2 induction had the opposite effects. Taken together, these results are supportive of an active crosstalk between the oncogenic Erk1/2 and STAT3 pathways in OSCC, the significance of which requires further investigation.

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“…Cyclin D1 is the key cell cycle control gene that facilitates the transition of cells from the G 1 phase into the S phase (18). A previous study demonstrated that inhibition of cyclin D1 could inhibit VSMC proliferation (30). The present study demonstrated that hypoxia increased the mRNA and protein expression of cyclin D1, whereas Gal-3 inhibition significantly reduced cyclin D1 expression.…”

Section: Discussionmentioning

confidence: 99%

Galectin-3 inhibition ameliorates hypoxia-induced pulmonary artery hypertension

Hao

2016

Molecular Medicine Reports

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Galectin-3 (Gal-3) is a β-galactoside-binding lectin, which is important in inflammation, fibrosis and heart failure. The present study aimed to investigate the role and mechanism of Gal-3 in hypoxia-induced pulmonary arterial hypertension (PAH). Male C57BL/6J and Gal-3−/− mice were exposed to hypoxia, then the right ventricular systolic pressure (RVSP) and Fulton's index were measured, and Gal-3 mRNA and protein expression in the pulmonary arteries was analyzed by reverse transcription-quantitative polymerase chain reaction and western blotting. Compared with the control, hypoxia increased the mRNA and protein expression levels of Gal-3 in wild type murine pulmonary arteries. Gal-3 deletion reduced the hypoxia-induced upregulation of RVSP and Fulton's index. Furthermore, human pulmonary arterial endothelial cells (HPAECs) and human pulmonary arterial smooth muscle cells (HPASMCs) were stimulated by hypoxia in vitro, and Gal-3 expression was inhibited by small interfering RNA. The inflammatory response of HPAECs, and the proliferation and cell cycle distribution of HPASMCs was also analyzed. Gal-3 inhibition alleviated the hypoxia-induced inflammatory response in HPAECs, including tumor necrosis factor-α and interleukin-1 secretion, expression of intercellular adhesion molecule-1 and adhesion of THP-1 monocytes. Gal-3 inhibition also reduced hypoxia-induced proliferation of HPASMCs, partially by reducing cyclin D1 expression and increasing p27 expression. Furthermore, Gal-3 inhibition suppressed HPASMC switching from a ‘contractile’ to a ‘synthetic’ phenotype. In conclusion, Gal-3 serves a fundamental role in hypoxia-induced PAH, and inhibition of Gal-3 may represent a novel therapeutic target for the treatment of hypoxia-induced PAH.

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Rho-associated protein kinase isoforms stimulate proliferation of vascular smooth muscle cells through ERK and induction of cyclin D1 and PCNA

Cited by 35 publications

References 22 publications

The Effects of Knockdown of Rho-Associated Kinase 1 and Zipper-Interacting Protein Kinase on Gene Expression and Function in Cultured Human Arterial Smooth Muscle Cells

The Effects of Knockdown of Rho-Associated Kinase 1 and Zipper-Interacting Protein Kinase on Gene Expression and Function in Cultured Human Arterial Smooth Muscle Cells

Erk1/2 activation and modulation of STAT3 signaling in oral cancer

Galectin-3 inhibition ameliorates hypoxia-induced pulmonary artery hypertension

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