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NFAT5/TonEBP Limits Pulmonary Vascular Resistance in the Hypoxic Lung by Controlling Mitochondrial Reactive Oxygen Species Generation in Arterial Smooth Muscle Cells.

ABSTRACT: Chronic hypoxia increases the resistance of pulmonary arteries by stimulating their contraction and augmenting their coverage by smooth muscle cells (SMCs). While these responses require adjustment of the vascular SMC transcriptome, regulatory elements are not well defined in this context. Here, we explored the functional role of the transcription factor nuclear factor of activated T-cells 5 (NFAT5/TonEBP) in the hypoxic lung. Regulatory functions of NFAT5 were investigated in cultured artery SMCs and lungs from control (Nfat5^fl/fl) and SMC-specific Nfat5-deficient (Nfat5^(SMC)-/-) mice. Exposure to hypoxia promoted the expression of genes associated with metabolism and mitochondrial oxidative phosphorylation (OXPHOS) in Nfat5^(SMC)-/- versus Nfat5^fl/fl lungs. In vitro, hypoxia-exposed Nfat5-deficient pulmonary artery SMCs elevated the level of OXPHOS-related transcripts, mitochondrial respiration, and production of reactive oxygen species (ROS). Right ventricular functions were impaired while pulmonary right ventricular systolic pressure (RVSP) was amplified in hypoxia-exposed Nfat5^(SMC)-/- versus Nfat5^fl/fl mice. Scavenging of mitochondrial ROS normalized the raise in RVSP. Our findings suggest a critical role for NFAT5 as a suppressor of OXPHOS-associated gene expression, mitochondrial respiration, and ROS production in pulmonary artery SMCs that is vital to limit ROS-dependent arterial resistance in a hypoxic environment.

SUBMITTER: Laban H

PROVIDER: S-EPMC8699676 | biostudies-literature |

REPOSITORIES: biostudies-literature

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TonEBP/NFAT5 regulates ACTBL2 expression in biomechanically activated vascular smooth muscle cells.

Project description:Cytoskeletal reorganization and migration are critical responses which enable vascular smooth muscle cells (VSMCs) cells to evade, compensate, or adapt to alterations in biomechanical stress. An increase in wall stress or biomechanical stretch as it is elicited by arterial hypertension promotes their reorganization in the vessel wall which may lead to arterial stiffening and contractile dysfunction. This adaptive remodeling process is dependent on and driven by subtle phenotype changes including those controlling the cytoskeletal architecture and motility of VSMCs. Recently, it has been reported that the transcription factor nuclear factor of activated T-cells 5 (TonEBP/NFAT5) controls critical aspects of the VSMC phenotype and is activated by biomechanical stretch. We therefore hypothesized that NFAT5 controls the expression of gene products orchestrating cytoskeletal reorganization in stretch-stimulated VSMCs. Automated immunofluorescence and Western blot analyses revealed that biomechanical stretch enhances the expression and nuclear translocation of NFAT5 in VSMCs. Subsequent in silico analyses suggested that this transcription factor binds to the promotor region of ACTBL2 encoding kappa-actin which was shown to be abundantly expressed in VSMCs upon exposure to biomechanical stretch. Furthermore, ACTBL2 expression was inhibited in these cells upon siRNA-mediated knockdown of NFAT5. Kappa-actin appeared to be aligned with stress fibers under static culture conditions, dispersed in lamellipodia and supported VSMC migration as its knockdown diminishes lateral migration of these cells. In summary, our findings delineated biomechanical stretch as a determinant of NFAT5 expression and nuclear translocation controlling the expression of the cytoskeletal protein ACTBL2. This response may orchestrate the migratory activity of VSMCs and thus promote maladaptive rearrangement of the arterial vessel wall during hypertension.

| S-EPMC4253659 | biostudies-literature

Genetic ablation of TonEBP/NFAT5 in smooth muscle cells inhibits arterial remodeling

Project description:Chronic biomechanical stress elicits remodeling of the arterial wall and causes detrimental arterial stenosis and stiffening. In this context, molecular determinants controlling proliferation and stress responses of vascular smooth muscle cells (VSMCs) have been insufficiently studied. We identified the transcription factor ‘nuclear factor of activated T-cells 5’ (NFAT5) as crucial regulatory element of mechanical stress responses of VSMCs. The relevance of this observation for biomechanically induced arterial remodeling was investigated in mice upon SMC-specific knockdown of NFAT5. While blood pressure levels, vascular architecture and flow-induced collateral growth were not affected in these mice, both hypertension-mediated arterial thickening and muscularization of pulmonary arteries during pulmonary artery hypertension (PAH) were impaired. In all models, a decrease in VSMC proliferation was observed indicating that NFAT5 controls activation of VSMCs in the remodeling arterial wall. Mechanistically, mechanoactivation of VSMCs promotes nuclear translocation NFTA5c upon its phosphorylation at Y143 and dephosphorylation at S1197. As evidenced by transcriptome studies, loss of NFAT5 in mechanoactivated VSMCs impairs expression of gene products controlling cell cycle and transcription/translation. These findings identify NFAT5 as molecular determinant of VSMC responses to biomechanical stress and arterial thickening.

2018-08-10 | GSE106274 | GEO

NFAT5/TonEBP controls metabolic adaption and tone of pulmonary vascular smooth muscle cells in the hypoxic lung

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-11-24 | GSE178468 | GEO

Arterial wall stress controls NFAT5 activity in vascular smooth muscle cells.

Project description:BackgroundNuclear factor of activated T-cells 5 (NFAT5) has recently been described to control the phenotype of vascular smooth muscle cells (VSMCs). Although an increase in wall stress or stretch (eg, elicited by hypertension) is a prototypic determinant of VSMC activation, the impact of this biomechanical force on the activity of NFAT5 is unknown. This study intended to reveal the function of NFAT5 and to explore potential signal transduction pathways leading to its activation in stretch-stimulated VSMCs.Methods and resultsHuman arterial VSMCs were exposed to biomechanical stretch and subjected to immunofluorescence and protein-biochemical analyses. Stretch promoted the translocation of NFAT5 to the nucleus within 24 hours. While the protein abundance of NFAT5 was regulated through activation of c-Jun N-terminal kinase under these conditions, its translocation required prior activation of palmitoyltransferases. DNA microarray and ChiP analyses identified the matrix molecule tenascin-C as a prominent transcriptional target of NFAT5 under these conditions that stimulates migration of VSMCs. Analyses of isolated mouse femoral arteries exposed to hypertensive perfusion conditions verified that NFAT5 translocation to the nucleus is followed by an increase in tenascin-C abundance in the vessel wall.ConclusionsCollectively, our data suggest that biomechanical stretch is sufficient to activate NFAT5 both in native and cultured VSMCs where it regulates the expression of tenascin-C. This may contribute to an improved migratory activity of VSMCs and thus promote maladaptive vascular remodeling processes such as hypertension-induced arterial stiffening.

| S-EPMC4187483 | biostudies-literature

NFAT5/TonEBP controls metabolic adaption and tone of pulmonary vascular smooth muscle cells in the hypoxic lung [SMC]

Project description:Hypoxia provokes adaptive responses of cells, which ensure their energy supply including the adjustment of the transcriptome to match their metabolism. In this context, we explored the transcriptional impact of nuclear factor of activated T-cells 5 (NFAT5) on the function of vascular smooth muscle cells (VSMC) in the hypoxic lung. Exposure to hypoxia induced a rapid nuclear translocation of NFAT5 in cultured murine VSMCs. SMC-specific ablation of Nfat5 (Nfat5(SMC-/-)) increases the systolic pressure in the right ventricle (RVSP) of the mouse heart and impairs its function upon exposure to hypoxia for 7 and 21 days. Analyses of the transcriptome of the lung revealed a robust increase in the expression genes attributed to mitochondrial respiration. Further analyses of hypoxia-exposed pulmonary artery VSMCs revealed that loss of Nfat5 stimulates the expression of multiple mitochondria-related genes encoding cytochrome oxidases while decreasing the expression of lactate dehydrogenase A (Ldha) and phosphofructokinase 3 (Pfkfb3). Both, inhibition of LDHA or PFKFB3 activity and loss of Nfat5 stimulated the mitochondrial production of reactive oxygen species (ROS) in hypoxic pulmonary artery VSMCs while scavenging of ROS normalized the RVSP values in hypoxia-exposed Nfat5(SMC-/-) mice. In summary, our findings suggest a crucial role for NFAT5 in adjusting the transcriptome of hypoxia-exposed pulmonary artery VSMCs to support an adequate glycolysis-centered metabolism. Loss of Nfat5 impairs this response thereby fueling the mitochondrial respiration and ROS production that amplifies the hypoxia-mediated constriction of pulmonary arteries.

2021-11-26 | GSE178463 | GEO

NFAT5/TonEBP controls metabolic adaption and tone of pulmonary vascular smooth muscle cells in the hypoxic lung [normoxia vs hypoxia]

2021-11-26 | GSE178462 | GEO

Genetic ablation of NFAT5/TonEBP in smooth muscle cells impairs flow- and pressure-induced arterial remodeling in mice

Project description:To study the impact of the transcription factor NFAT5 on the vascular smooth muscle cell (VSMC) transcriptome, genetic ablation of floxed nfat5 in mouse aortic smooth muscle cells was achieved by transducing them with an adenoviral vector to express Cre-recombinase (Ad-Cre) under control of a CMV promoter. Empty vector adenovirus (Ad-PL) was used as control.

2018-10-10 | GSE109864 | GEO

Genetic ablation of TonEBP/NFAT5 in smooth muscle cells inhibits arterial remodeling

Project description:Genetic ablation of TonEBP/NFAT5 in smooth muscle cells inhibits arterial remodeling

| PRJNA416108 | ENA

Reactive oxygen species regulate context-dependent inhibition of NFAT5 target genes.

Project description:The activation of nuclear factor of activated T cells 5 (NFAT5), a well-known osmoprotective factor, can be induced by isotonic stimuli, such as activated Toll-like receptors (TLRs). It is unclear, however, how NFAT5 discriminates between isotonic and hypertonic stimuli. In this study we identified a novel context-dependent suppression of NFAT5 target gene expression in RAW 264.7 macrophages stimulated with lipopolysaccharide (LPS) or a high salt (NaCl) concentration. Although LPS and NaCl both used NFAT5 as a core transcription factor, these stimuli mutually inhibited distinct sets of NFAT5 targets within the cells. Although reactive oxygen species (ROS) are essential for this inhibition, the source of ROS differed depending on the context: mitochondria for high salt and xanthine oxidase for TLRs. Specifically, the high salt-induced suppression of interleukin-6 (IL-6) production was mediated through the ROS-induced inhibition of NFAT5 binding to the IL-6 promoter. The context-dependent inhibition of NFAT5 target gene expression was also confirmed in mouse spleen and kidney tissues that were cotreated with LPS and high salt. Taken together, our data suggest that ROS function as molecular sensors to discriminate between TLR ligation and osmotic stimuli in RAW 264.7 macrophages, directing NFAT5 activity toward proinflammatory or hypertonic responses in a context-dependent manner.

| S-EPMC3731662 | biostudies-literature

LPS-induced NFκB enhanceosome requires TonEBP/NFAT5 without DNA binding.

Project description:NFκB is a central mediator of inflammation. Present inhibitors of NFκB are mostly based on inhibition of essential machinery such as proteasome and protein kinases, or activation of nuclear receptors; as such, they are of limited therapeutic use due to severe toxicity. Here we report an LPS-induced NFκB enhanceosome in which TonEBP is required for the recruitment of p300. Increased expression of TonEBP enhances the NFκB activity and reduced TonEBP expression lowers it. Recombinant TonEBP molecules incapable of recruiting p300 do not stimulate NFκB. Myeloid-specific deletion of TonEBP results in milder inflammation and sepsis. We discover that a natural small molecule cerulenin specifically disrupts the enhanceosome without affecting the activation of NFκB itself. Cerulenin suppresses the pro-inflammatory activation of macrophages and sepsis without detectable toxicity. Thus, the NFκB enhanceosome offers a promising target for useful anti-inflammatory agents.

| S-EPMC4847014 | biostudies-literature

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