Down-Regulation of Protein Kinase C-ε by Prolonged Incubation with PMA Inhibits the Proliferation of Vascular Smooth Muscle Cells

Zhou, Huixuan; Wang, Yan; Zhou, Quanhong; Wu, Bin; Wang, Aizhong; Jiang, Wei; Wang, Li

doi:10.1159/000452553

Cited by 7 publications

(6 citation statements)

References 42 publications

(52 reference statements)

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“…HPASMCs were cultured in Smooth Muscle Growth Medium-2 (SmGM™-2, Lonza). The proliferation of HPASMCs was evaluated using both the Cell Counting Kit-8 (CCK-8) and Bromodeoxyuridine (BrdU) ELISA kit as previously described, respectively (18, 19). HPASMCs were treated with multiple growth factors, specifically 5% fetal calf serum, PDGF-BB (30 ng/mL), FGF2 (2 ng/mL), epidermal growth factor (EGF) (0.5 ng/mL), and insulin-like growth factor-1 (IGF-1) (0.5 μg/mL) with or without imatinib (3 μM) or nintedanib (0.3 μM).…”

Section: Methodsmentioning

confidence: 99%

Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation

Tsutsumi

Nagaoka

Yoshida

et al. 2019

Preprint

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Neointimal lesion and medial wall thickness of pulmonary arteries (PAs) are common pathological findings in pulmonary arterial hypertension (PAH). Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling contribute to intimal and medial vascular remodeling in PAH. Nintedanib is a tyrosine kinase inhibitor whose targets include PDGF and FGF receptors. Although the beneficial effects of nintedanib were demonstrated for human idiopathic pulmonary fibrosis, its efficacy for PAH is still unclear. Thus, we hypothesized that nintedanib is a novel treatment for PAH to inhibit the progression of vascular remodeling in PAs. The inhibitory effects of nintedanib were evaluated both in endothelial mesenchymal transition (EndMT)-induced human pulmonary microvascular endothelial cells (HPMVECs) and human pulmonary arterial smooth muscle cells (HPASMCs) stimulated by growth factors. We also tested the effect of chronic nintedanib administration on a PAH rat model induced by Sugen5416 (a VEGF receptor inhibitor) combined with chronic hypoxia. Nintedanib was administered from weeks 3 to 5 after Sugen5416 injection, and pulmonary hemodynamics and PAs pathology were evaluated. Nintedanib attenuated the expression of mesenchymal markers in EndMT-induced HPMVECs and HPASMCs proliferation. Phosphorylation of PDGF and FGF receptors was augmented both in both intimal and medial lesions of PAs. Nintedanib blocked these phosphorylation, improved hemodynamics and reduced vascular remodeling involving neointimal lesions and medial wall thickening in PAs. Additionally, expressions Twist1, transcription factors associated with EndMT, in lung tissue was significantly reduced by nintedanib. These results suggest that nintedanib may be a novel treatment for PAH with anti-vascular remodeling effects.

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Section: Methodsmentioning

confidence: 99%

Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation

Tsutsumi

Nagaoka

Yoshida

et al. 2019

Preprint

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“…VSMC proliferation was evaluated by Cell Counting Kit-8 (CCK-8) and EdU incorporation assay [35, 36]. Cell counting kit-8 kits (CCK-8, Beyotime Institute of Biotechnology, Shanghai, China) was used according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

NLRP3 Gene Deletion Attenuates Angiotensin II-Induced Phenotypic Transformation of Vascular Smooth Muscle Cells and Vascular Remodeling

Ren

Tong

et al. 2017

Cell Physiol Biochem

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Background/Aims: Angiotensin (Ang) II plays vital roles in vascular inflammation and remodeling in hypertension. Phenotypic transformation of vascular smooth muscle cells (VSMCs) is a major initiating factor for vascular remodeling. The present study was designed to determine the roles of NLRP3 inflammasome activation in Ang II-induced VSMC phenotypic transformation and vascular remodeling in hypertension. Methods: Primary VSMCs from the aorta of NLRP3 knockout (NLRP3^-/-) mice and wild-type (WT) mice were treated with Ang II for 24 h. Subcutaneous infusion of Ang II via osmotic minipump for 2 weeks was used to induce vascular remodeling and hypertension in WT and NLRP3^-/- mice. Results: NLRP3 gene deletion attenuates Ang II-induced NLRP3 inflammasome activation, phenotypic transformation from a contractile phenotype to a synthetic phenotype and proliferation in primary mice VSMCs. Ang II-induced hypertension and vascular remodeling in WT mice were attenuated in NLRP3^-/- mice. Furthermore, Ang II-induced NLRP3 inflammasome activation, phenotypic transformation and proliferating cell nuclear antigen (PCNA) upregulation were inhibited in the media of aorta of NLRP3^-/- mice. Conclusions: NLRP3 inflammasome activation contributes to Ang II-induced VSMC phenotypic transformation and proliferation as well as vascular remodeling and hypertension.

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“…In rat models of aortic balloon injury, the PKCε activator ψεRACK promotes neointimal development, while the PKCε inhibitor εV1-2 reduces luminal narrowing, neointimal proliferation, VSMC ERK phosphorylation, and PDGF-induced VSMC proliferation/migration [433]. Repeated stimulation with phorbol myristate acetate (PMA) downregulates PKCε and inhibits VSMC proliferation [434].…”

Section: Vsm Dysfunction and Vascular Diseasementioning

confidence: 99%

Evolving mechanisms of vascular smooth muscle contraction highlight key targets in vascular disease

Liu

Khalil

2018

Biochemical Pharmacology

113

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Vascular smooth muscle (VSM) plays an important role in the regulation of vascular function. Identifying the mechanisms of VSM contraction has been a major research goal in order to determine the causes of vascular dysfunction and exaggerated vasoconstriction in vascular disease. Major discoveries over several decades have helped to better understand the mechanisms of VSM contraction. Ca has been established as a major regulator of VSM contraction, and its sources, cytosolic levels, homeostatic mechanisms and subcellular distribution have been defined. Biochemical studies have also suggested that stimulation of Gq protein-coupled membrane receptors activates phospholipase C and promotes the hydrolysis of membrane phospholipids into inositol 1,4,5-trisphosphate (IP) and diacylglycerol (DAG). IP stimulates initial Ca release from the sarcoplasmic reticulum, and is buttressed by Ca influx through voltage-dependent, receptor-operated, transient receptor potential and store-operated channels. In order to prevent large increases in cytosolic Ca concentration ([Ca]), Ca removal mechanisms promote Ca extrusion via the plasmalemmal Ca pump and Na/Ca exchanger, and Ca uptake by the sarcoplasmic reticulum and mitochondria, and the coordinated activities of these Ca handling mechanisms help to create subplasmalemmal Ca domains. Threshold increases in [Ca] form a Ca-calmodulin complex, which activates myosin light chain (MLC) kinase, and causes MLC phosphorylation, actin-myosin interaction, and VSM contraction. Dissociations in the relationships between [Ca], MLC phosphorylation, and force have suggested additional Ca sensitization mechanisms. DAG activates protein kinase C (PKC) isoforms, which directly or indirectly via mitogen-activated protein kinase phosphorylate the actin-binding proteins calponin and caldesmon and thereby enhance the myofilaments force sensitivity to Ca. PKC-mediated phosphorylation of PKC-potentiated phosphatase inhibitor protein-17 (CPI-17), and RhoA-mediated activation of Rho-kinase (ROCK) inhibit MLC phosphatase and in turn increase MLC phosphorylation and VSM contraction. Abnormalities in the Ca handling mechanisms and PKC and ROCK activity have been associated with vascular dysfunction in multiple vascular disorders. Modulators of [Ca], PKC and ROCK activity could be useful in mitigating the increased vasoconstriction associated with vascular disease.

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Down-Regulation of Protein Kinase C-ε by Prolonged Incubation with PMA Inhibits the Proliferation of Vascular Smooth Muscle Cells

Cited by 7 publications

References 42 publications

Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation

Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation

NLRP3 Gene Deletion Attenuates Angiotensin II-Induced Phenotypic Transformation of Vascular Smooth Muscle Cells and Vascular Remodeling

Evolving mechanisms of vascular smooth muscle contraction highlight key targets in vascular disease

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