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TGF-? and restenosis revisited: a Smad link.

ABSTRACT: Despite novel surgical therapies for the treatment of atherosclerosis, restenosis continues to be a significant impediment to the long-term success of vascular interventions. Transforming growth factor-beta (TGF-?), a family of cytokines found to be up-regulated at sites of arterial injury, has long been implicated in restenosis; a role that has largely been attributed to TGF-?-mediated vascular fibrosis. However, emerging data indicate that the role of TGF-? in intimal thickening and arterial remodeling, the critical components of restenosis, is complex and multidirectional. Recent advancements have clarified the basic signaling pathway of TGF-?, making evident the need to redefine the precise role of this family of cytokines and its primary signaling pathway, Smad, in restenosis. Unraveling TGF-? signaling in intimal thickening and arterial remodeling will pave the way for a clearer understanding of restenosis and the development of innovative pharmacological therapies.

SUBMITTER: Suwanabol PA

PROVIDER: S-EPMC3077463 | biostudies-other | 2011 May

REPOSITORIES: biostudies-other

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TGF-β and restenosis revisited: a Smad link.

Suwanabol Pasithorn A PA Kent K Craig KC Liu Bo B

The Journal of surgical research 20110115 2

Despite novel surgical therapies for the treatment of atherosclerosis, restenosis continues to be a significant impediment to the long-term success of vascular interventions. Transforming growth factor-beta (TGF-β), a family of cytokines found to be up-regulated at sites of arterial injury, has long been implicated in restenosis; a role that has largely been attributed to TGF-β-mediated vascular fibrosis. However, emerging data indicate that the role of TGF-β in intimal thickening and arterial r ...[more]

PMID: 21324395

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Project description:The effect of endogenous progesterone and/or exogenous pre- or postnatal progesterone application on lung function of preterm infants is poorly defined. While prenatal progesterone substitution may prevent preterm birth, in vitro and in vivo data suggest a benefit of postnatal progesterone replacement on the incidence and severity of bronchopulmonary dysplasia (BPD). However, the molecular mechanisms responsible for progesterone's effects are undefined. Numerous factors are involved in lung development, airway inflammation, and airway remodeling: the transforming growth factor beta (TGF-?)/mothers against decapentaplegic homolog (Smad) signaling pathway and TGF-?-regulated genes, such as connective tissue growth factor (CTGF), transgelin (TAGLN), and plasminogen activator inhibitor-1 (PAI-1). These processes contribute to the development of BPD. The aim of the present study was to clarify whether progesterone could affect TGF-?1-activated Smad signaling and CTGF/transgelin/PAI-1 expression in lung epithelial cells. The pharmacological effect of progesterone on Smad signaling was investigated using a TGF-?1-inducible luciferase reporter and western blotting analysis of phosphorylated Smad2/3 in A549 lung epithelial cells. The regulation of CTGF, transgelin, and PAI-1 expression by progesterone was studied using a promoter-based luciferase reporter, quantitative real-time PCR, and western blotting in the same cell line. While progesterone alone had no direct effect on Smad signaling in lung epithelial cells, it dose-dependently inhibited TGF-?1-induced Smad3 phosphorylation, as shown by luciferase assays and western blotting analysis. Progesterone also antagonized the TGF-?1/Smad-induced upregulation of CTGF, transgelin, and PAI-1 at the promoter, mRNA, and/or protein levels. The present study highlights possible new molecular mechanisms involving progesterone, including inhibition of TGF-?1-activated Smad signaling and TGF-?1-regulated genes involved in BPD pathogenesis, which are likely to attenuate the development of BPD by inhibiting TGF-?1-mediated airway remodeling. Understanding these mechanisms might help to explain the effects of pre- or postnatal application of progesterone on lung diseases of preterm infants.

Project description:BackgroundGlioblastoma multiforme (GBM) is characterized by lethal aggressiveness and patients with GBM are in urgent need for new therapeutic avenues to improve quality of life. Current studies on tumor invasion focused on roles of cytokines in tumor microenvironment and numerous evidence suggests that TGF-β2 is abundant in glioma microenvironment and vital for glioma invasion. Autopagy is also emerging as a critical factor in aggressive behaviors of cancer cells; however, the relationship between TGF-β2 and autophagy in glioma has been poorly understood.MethodsU251, T98 and U87 GBM cell lines as well as GBM cells from a primary human specimen were used in vitro and in vivo to evaluate the effect of TGF-β2 on autophagy. Western blot, qPCR, immunofluorescence and transmission-electron microscope were used to detect target molecular expression. Lentivirus and siRNA vehicle were introduced to establish cell lines, as well as mitotracker and seahorse experiment to study the metabolic process in glioma. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models.ResultsHere we demonstrated that TGF-β2 activated autophagy in human glioma cell lines and knockdown of Smad2 or inhibition of c-Jun NH2-terminal kinase, attenuated TGF-β2-induced autophagy. TGF-β2-induced autophagy is important for glioma invasion due to the alteration of epithelial-mesenchymal transition and metabolism conversion, particularly influencing mitochondria trafficking and membrane potential (△Ψm). Autopaghy also initiated a feedback on TGF-β2 in glioma by keeping its autocrine loop and affecting Smad2/3/7 expression. A xenograft model provided additional confirmation on combination of TGF-β inhibitor (Galunisertib) and autophagy inhibitor (CQ) to better "turn off" tumor growth.ConclusionOur findings elucidated a potential mechanism of autophagy-associated glioma invasion that TGF-β2 could initiate autophagy via Smad and non-Smad pathway to promote glioma cells' invasion.

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TGF-? and restenosis revisited: a Smad link.

Publications

TGF-β and restenosis revisited: a Smad link.

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