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G-protein-coupled receptor kinase interacting protein-1 mediates intima formation by regulating vascular smooth muscle proliferation, apoptosis, and migration.

ABSTRACT: The G-protein-coupled receptor kinase interacting protein-1 (GIT1) is a scaffold protein that is important for phospholipase C? and extracellular signal-regulated kinase 1/2 signaling induced by angiotensin II and epidermal growth factor. Because GIT1 regulates signaling by several vascular smooth muscle cell (VSMC) growth factors, we hypothesized that intima formation would be inhibited by GIT1 depletion.Complete carotid ligation was performed on GIT1 wild-type and knockout (KO) mice. We compared changes between GIT1 wild-type and KO mice in carotid vascular remodeling, VSMC proliferation, and apoptosis in vivo and in vitro. Our data demonstrated that GIT1 deficiency significantly decreased intima formation after carotid ligation as a result of both reduced VSMC proliferation and enhanced apoptosis. To confirm the effects of GIT1 in vitro, we performed proliferation and apoptosis assays in VSMC. In mouse aortic smooth muscle cells (MASM), we found that the growth rate and [3H]-thymidine incorporation of the GIT1 KO MASM were significantly decreased compared with the wild-type MASM. Cyclin D1, which is a key cell cycle regulator, was significantly decreased in GIT1 KO cells. Serum deprivation of GIT1 KO MASM increased apoptosis 3-fold compared with wild-type MASM. Treatment of rat aortic smooth muscle cells with GIT1 small interfering RNA impaired cell migration. Both phospholipase C? and extracellular signal-regulated kinase 1/2 signaling were required for GIT1-dependent VSMC proliferation and migration, whereas only phospholipase C? was involved in GIT1-mediated VSMC apoptosis.GIT1 is a novel mediator of vascular remodeling by regulating VSMC proliferation, migration, and apoptosis through phospholipase C? and extracellular signal-regulated kinase 1/2 signaling pathways.

SUBMITTER: Pang J

PROVIDER: S-EPMC3703521 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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G-protein-coupled receptor kinase interacting protein-1 mediates intima formation by regulating vascular smooth muscle proliferation, apoptosis, and migration.

Pang Jinjiang J Xu Xiangbin X Wang Xiaoqun X Majumder Syamantak S Wang Jing J Korshunov Vyacheslav A VA Berk Bradford C BC

Arteriosclerosis, thrombosis, and vascular biology 20130221 5

<h4>Objective</h4>The G-protein-coupled receptor kinase interacting protein-1 (GIT1) is a scaffold protein that is important for phospholipase Cγ and extracellular signal-regulated kinase 1/2 signaling induced by angiotensin II and epidermal growth factor. Because GIT1 regulates signaling by several vascular smooth muscle cell (VSMC) growth factors, we hypothesized that intima formation would be inhibited by GIT1 depletion.<h4>Approach and results</h4>Complete carotid ligation was performed on G ...[more]

PMID: 23430614

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Project description:BackgroundVascular remodelling is an essential pathophysiological state in many circulatory diseases. Abnormal vascular smooth muscle cell (VSMC) behaviour leads to neointimal formation and may eventually results in major adverse cardiovascular events. The C1q/TNF-related protein (C1QTNF) family is closely associated with cardiovascular disease. Notably, C1QTNF4 has unique two C1q domains. However, the role of C1QTNF4 in vascular diseases remains unclear.MethodsC1QTNF4 expression was detected in human serum and artery tissues using ELISA and multiplex immunofluorescence (mIF) staining. Scratch assay, transwell assay and confocal microscopy were used to investigate C1QTNF4 effects on VSMC migration. EdU incorporation, MTT assay and cell counting experiment revealed C1QTNF4 effects on VSMC proliferation. C1QTNF4-transgenic, C1QTNF4-/- and AAV9-mediated VSMC-specific C1QTNF4 restoration C1QTNF4-/- mouse and rat disease models were generated. RNA-seq, quantitative real-time PCR, western blot, mIF, proliferation and migration assays were used to investigate the phenotypic characteristics and underlying mechanisms.ResultsSerum C1QTNF4 levels were decreased in patients with arterial stenosis. C1QTNF4 shows colocalisation with VSMC in human renal arteries. In vitro, C1QTNF4 inhibits VSMC proliferation and migration and alters VSMC phenotype. In vivo, an adenovirus-infected rat balloon injury model, C1QTNF4-transgenic and C1QTNF4-/- mouse wire-injury models with or without VSMC-specific C1QTNF4 restoration were established to mimic the VSMC repair and remodelling. The results show that C1QTNF4 decreases intimal hyperplasia. Especially, we displayed the rescue effect of C1QTNF4 in vascular remodelling using AAV vectors. Next, transcriptome analysis of artery tissue identified the potential mechanism. In vitro and in vivo experiments confirm that C1QTNF4 ameliorates neointimal formation and maintains vascular morphology by downregulating the FAK/PI3K/AKT pathway.ConclusionsOur study demonstrated that C1QTNF4 is a novel inhibitor of VSMC proliferation and migration that acts by downregulating the FAK/PI3K/AKT pathway, thus protecting blood vessels from abnormal neointima formation. These results provide new insights into promising potent treatments for vascular stenosis diseases.

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G-protein-coupled receptor kinase interacting protein-1 mediates intima formation by regulating vascular smooth muscle proliferation, apoptosis, and migration.

Publications

G-protein-coupled receptor kinase interacting protein-1 mediates intima formation by regulating vascular smooth muscle proliferation, apoptosis, and migration.

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