Spry1 and Spry4 Differentially Regulate Human Aortic Smooth Muscle Cell Phenotype via Akt/FoxO/Myocardin Signaling

Yang, Xuehui; Gong, Yan; Tang, Yun‐Chi; Li, Hongfang; He, Qing; Gower, Lindsey; Liaw, Lucy; Friesel, Robert

doi:10.1371/journal.pone.0058746

Cited by 45 publications

(53 citation statements)

References 36 publications

(40 reference statements)

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“…When PI3K is activated, it generates a second messenger in the cell membrane: PIP 3 , which binds to and activates Akt. Akt, also known as protein kinase B (PKB), has a relatively large molecular mass of 60,000 Da and phosphorylates a variety of transcription factors directly and can therefore inhibit apoptosis gene expression and enhance the anti-apoptotic gene expression, thereby promoting cell survival [1,26]. In the present study, we first confirmed that the Ox-LDL-mediated proliferation was via the PI3K/ Akt and MAPK/ERK pathways.…”

Section: Discussionsupporting

confidence: 67%

“…The mechanisms of Ox-LDL-induced macrophage proliferation are complex and include processes such as an increase in intracellular calcium, activation of protein kinase C (PKC), and secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) [35][36][37]. PI3K/Akt and MAPK/ERK are believed to be involved in downstream signaling [4,26,38]. The MAPK signaling pathway includes ERK, JNK and p38 MAPK; the ERK pathway is the most common cell proliferative response-mediated signaling pathway [1,39].…”

Section: Discussionmentioning

confidence: 99%

“…PI3K/Akt and MAPK/ERK are known to be important signaling molecules in cell proliferation, migration and apoptosis [1,12,16,26]. Consistent with previous studies [4,6,27,28], our results showed that the Ox-LDL-mediated proliferation was via the PI3K/Akt and MAPK/ERK pathways because in the presence of PI3K/Akt or MAPK/ERK inhibitors, PD98059 (10 -7 M) and LY294002 (10 -5 M), respectively, the Ox-LDL (20 µg/ml)-mediated…”

Section: Role Of Pi3k/akt and Mapk/erk Signaling Pathways In The Inhimentioning

confidence: 99%

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Dopamine D1-Like Receptors Suppress the Proliferation of Macrophages Induced by Ox-LDL

Yao

Yang

Han

et al. 2016

Cell Physiol Biochem

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Background/Aims: Oxidized low-density lipoprotein (Ox-LDL) induces macrophage proliferation, a key physiological process which leads to atherosclerosis. The aim of this study was to determine the effects of dopamine D₁-like receptors on macrophage proliferation induced by Ox-LDL. Methods: The expression of dopamine D₁-like receptors was determined by immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblotting. The effect of D₁-like receptors on macrophage proliferation induced by Ox-LDL was measured by ³[H]-thymidine incorporation and cell number count. Results: Dopamine D₁-like receptors were present in macrophages as determined by immunohistochemistry, RT-PCR and immunoblotting. A D₁-like receptor agonist, fenoldopam, which by itself had no effect on macrophage proliferation, inhibited the stimulatory effect of Ox-LDL on macrophage proliferation. This was further confirmed by the D₁-like receptor antagonist SCH 23390 blocking the effect of fenoldopam, thereby indicating that the fenoldopam action was receptor specific. Phosphatidylinositol 3-kinase (PI3K/Akt) and mitogen-activated protein kinase (MAPK/ERK) pathways were also involved in the proliferative effect of Ox-LDL because in the presence of PI3K/Akt or MAPK/ERK inhibitors, LY294002 or PD98059, the stimulatory effects of Ox-LDL were blocked. Moreover, the stimulatory effect of Ox-LDL on the phosphorylation of ERK and Akt was significantly reduced by fenoldopam in macrophages. Additional experiments found that both D₁ and D₅ receptor expression was lower in the peritoneal macrophages from Apolipoprotein E-deficient mice compared to the control C57Bl/6J mice. Conclusions: Macrophages express D₁-like receptors. The activation of the D₁-like receptors significantly inhibits Ox-LDL-induced macrophage proliferation, possibly through the inhibition of the PI3K/Akt and MAPK/ERK signaling pathways.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Role Of Pi3k/akt and Mapk/erk Signaling Pathways In The Inhimentioning

confidence: 99%

See 1 more Smart Citation

Dopamine D1-Like Receptors Suppress the Proliferation of Macrophages Induced by Ox-LDL

Yao

Yang

Han

et al. 2016

Cell Physiol Biochem

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“…In a rat carotid artery injury model, treatment of injured vessels with a chimeric protein consisting of the HIV TAT membrane translocation sequence and Spry2 (TAT-hSpry2) inhibited neointima formation and VSMC proliferation for up to 28 days post injury [72]. Furthermore, in vitro studies on VSMC show that Spry1 and Spry4 have different roles in VSMC phenotypic modulation; Spry1 maintains the VSMC contractile phenotype in part by regulating an Akt/FoxO/myocardin pathway [59]. Together, these data show that Spry family members function to maintain proper levels of RTK signaling during vascular development, the vascular response to injury and vascular homeostasis.…”

Section: Fgf Signaling In Endothelial Cells Angiogenesis and Neovasmentioning

confidence: 99%

Fibroblast Growth Factor Signaling in the Vasculature

Yang

Liaw

Prudovsky

et al. 2015

Curr Atheroscler Rep

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Despite their discovery as angiogenic factors and mitogens for endothelial cells more than 30 years ago, much remains to be determined about the role of fibroblast growth factors (FGFs) and their receptors in vascular development, homeostasis, and disease. In vitro studies show that members of the FGF family stimulate growth, migration, and sprouting of endothelial cells, and growth, migration, and phenotypic plasticity of vascular smooth muscle cells. Recent studies have revealed important roles for FGFs and their receptors in the regulation of endothelial cell sprouting and vascular homeostasis in vivo. Furthermore, recent work has revealed roles for FGFs in atherosclerosis, vascular calcification, and vascular dysfunction. The large number of FGFs and their receptors expressed in endothelial and vascular smooth muscle cells complicates these studies. In this review, we summarize recent studies in which new and unanticipated roles for FGFs and their receptors in the vasculature have been revealed.

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“…Yang et al reported that FOXO3a regulates the gene transcription of myocardin, which participates in VSMC phenotypic modulation [16]. FOXO3a and its downstream gene, apoptotic protease activating factor 1, play important roles in VSMC survival during vessel remodeling and atherogenesis [17].…”

Section: Introductionmentioning

confidence: 99%

SIRT1 and FOXO Mediate Contractile Differentiation of Vascular Smooth Muscle Cells under Cyclic Stretch

Huang

Yan

Zhao

et al. 2015

Cell Physiol Biochem

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Background/Aims: Physiological mechanical stretch in vivo helps to maintain the quiescent contractile differentiation of vascular smooth muscle cells (VSMCs), but the underlying mechanisms are still unclear. Here, we investigated the effects of SIRT1 in VSMC differentiation in response to mechanical cyclic stretch. Methods and Results: Rat VSMCs were subjected to 10%-1.25Hz-cyclic stretch in vitro using a FX-4000T system. The data indicated that the expression of contractile markers, including α-actin, calponin and SM22α, was significantly enhanced in VSMCs that were subjected to cyclic stretch compared to the static controls. The expression of SIRT1 and FOXO3a was increased by the stretch, but the expression of FOXO4 was decreased. Decreasing SIRT1 by siRNA transfection attenuated the stretch-induced expression of contractile VSMC markers and FOXO3a. Furthermore, increasing SIRT1 by either treatment with activator resveratrol or transfection with a plasmid to induce overexpression increased the expression of FOXO3a and contractile markers, and decreased the expression of FOXO4 in VSMCs. Similar trends were observed in VSMCs of SIRT1 (+/-) knockout mice. The overexpression of FOXO3a promoted the expression of contractile markers in VSMCs, while the overexpression of FOXO4 demonstrated the opposite effect. Conclusion: Our results indicated that physiological cyclic stretch promotes the contractile differentiation of VSMCs via the SIRT1/FOXO pathways and thus contributes to maintaining vascular homeostasis.

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Spry1 and Spry4 Differentially Regulate Human Aortic Smooth Muscle Cell Phenotype via Akt/FoxO/Myocardin Signaling

Cited by 45 publications

References 36 publications

Dopamine D1-Like Receptors Suppress the Proliferation of Macrophages Induced by Ox-LDL

Dopamine D1-Like Receptors Suppress the Proliferation of Macrophages Induced by Ox-LDL

Fibroblast Growth Factor Signaling in the Vasculature

SIRT1 and FOXO Mediate Contractile Differentiation of Vascular Smooth Muscle Cells under Cyclic Stretch

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