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Bone morphogenetic protein signaling in vascular disease: anti-inflammatory action through myocardin-related transcription factor A.

ABSTRACT: Pulmonary artery hypertension (PAH) patients exhibit elevated levels of inflammatory cytokines and infiltration of inflammatory cells in the lung. Concurrently, mutations of bmpr2, the gene encoding the type II receptor of bone morphogenetic proteins (BMP), are found in ?75% of patients with familial PAH, but a possible nexus between increased inflammation and diminished BMP signaling has hitherto remained elusive. We previously showed that BMP4 triggers nuclear localization of the Myocardin-related transcription factor A (MRTF-A) in human pulmonary artery smooth muscle cells (PASMC), resulting in the induction of contractile proteins. Here we report the BMPR2-dependent repression of a set of inflammatory mediators in response to BMP4 stimulation of PASMC. Forced expression of MRTF-A precisely emulates the anti-inflammatory effect of BMP4, while MRTF-A depletion precludes BMP4-mediated cytokine inhibition. BMP4 and MRTF-A block signaling through NF-?B, the keystone of most pathways leading to inflammatory responses, at the level of chromatin recruitment and promoter activation. Moreover, MRTF-A physically interacts with RelA/p65, the NF-?B subunit endowed with a transcription activation domain. Interestingly, the MRTF-A-NF-?B interaction is mutually antagonistic: stimulation of NF-?B signaling by TNF?, as well as p65 overexpression, hinders MRTF-A activity and the expression of contractile genes. Thus, a molecular inhibitory pathway linking BMP4 signaling, activation of MRTF-A, and inhibition of NF-?B provides insights into the etiology of PAH and a potential focus of therapeutic intervention.

SUBMITTER: Wang D

PROVIDER: S-EPMC3431673 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Bone morphogenetic protein signaling in vascular disease: anti-inflammatory action through myocardin-related transcription factor A.

Wang Dahai D Prakash Jamunabai J Nguyen Peter P Davis-Dusenbery Brandi N BN Hill Nicholas S NS Layne Matthew D MD Hata Akiko A Lagna Giorgio G

The Journal of biological chemistry 20120620 33

Pulmonary artery hypertension (PAH) patients exhibit elevated levels of inflammatory cytokines and infiltration of inflammatory cells in the lung. Concurrently, mutations of bmpr2, the gene encoding the type II receptor of bone morphogenetic proteins (BMP), are found in ∼75% of patients with familial PAH, but a possible nexus between increased inflammation and diminished BMP signaling has hitherto remained elusive. We previously showed that BMP4 triggers nuclear localization of the Myocardin-rel ...[more]

PMID: 22718766

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Project description:Background & aimsBone morphogenetic protein (BMP)4 is a mesenchymal peptide that regulates cells of the gastric epithelium. We investigated whether BMP signaling pathways affect gastric inflammation after bacterial infection of mice.MethodsWe studied transgenic mice that express either the BMP inhibitor noggin or the β- galactosidase gene under the control of a BMP-responsive element and BMP4(βgal/+) mice. Gastric inflammation was induced by infection of mice with either Helicobacter pylori or Helicobacter felis. Eight to 12 weeks after inoculation, gastric tissue samples were collected and immunohistochemical, quantitative, reverse-transcription polymerase chain reaction and immunoblot analyses were performed. We used enzyme-linked immunosorbent assays to measure cytokine levels in supernatants from cultures of mouse splenocytes and dendritic cells, as well as from human gastric epithelial cells (AGS cell line). We also measured the effects of BMP-2, BMP-4, BMP-7, and the BMP inhibitor LDN-193189 on the expression of interleukin (IL)8 messenger RNA by AGS cells and primary cultures of canine parietal and mucus cells. The effect of BMP-4 on NFkB activation in parietal and AGS cells was examined by immunoblot and luciferase assays.ResultsTransgenic expression of noggin in mice increased H pylori- or H felis-induced inflammation and epithelial cell proliferation, accelerated the development of dysplasia, and increased expression of the signal transducer and activator of transcription 3 and activation-induced cytidine deaminase. BMP-4 was expressed in mesenchymal cells that expressed α-smooth muscle actin and activated BMP signaling pathways in the gastric epithelium. Neither BMP-4 expression nor BMP signaling were detected in immune cells of C57BL/6, BRE-β-galactosidase, or BMP-4(βgal/+) mice. Incubation of dendritic cells or splenocytes with BMP-4 did not affect lipopolysaccharide-stimulated production of cytokines. BMP-4, BMP-2, and BMP-7 inhibited basal and tumor necrosis factor α-stimulated expression of IL8 in canine gastric epithelial cells. LDN-193189 prevented BMP4-mediated inhibition of basal and tumor necrosis factor α-stimulated expression of IL8 in AGS cells. BMP-4 had no effect on TNFα-stimulated phosphorylation and degradation of IκBα, or on TNFα induction of a NFκβ reporter gene.ConclusionsBMP signaling reduces inflammation and inhibits dysplastic changes in the gastric mucosa after infection of mice with H pylori or H felis.

Dataset Information

Bone morphogenetic protein signaling in vascular disease: anti-inflammatory action through myocardin-related transcription factor A.

Publications

Bone morphogenetic protein signaling in vascular disease: anti-inflammatory action through myocardin-related transcription factor A.

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