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

Arnold, Caroline; Feldner, Anja; Zappe, Maren; Komljenovic, Dorde; Torre, Carolina De La; Ruzicka, Philipp; Hecker, Markus; Neuhofer, Wolfgang; Korff, Thomas

doi:10.1096/fj.201801594r

Cited by 8 publications

(24 citation statements)

References 65 publications

(73 reference statements)

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“…28 For VSMCs, our former studies showed that NFAT5 acts on the transcriptional level to promote the expression of biomechanical stress-regulated genes, which control the formation of focal adhesions and the organization of the cytoskeleton. 11 In fact, loss of Nfat5 impairs stress fiber formation as a prototypic stabilizing F I G U R E 4 Genetic ablation of Nfat5 and its effect on cholesterol-exposed VSMCs. Genetic ablation of Nfat5 was achieved by expressing Cre-recombinase in murine Nfat5 fl/fl VSMCs via adenoviral transduction (AdCre, an empty vector adenovirus (AdPl) served as control).…”

Section: Discussionmentioning

confidence: 99%

“…Along these lines, our former studies identified NFAT5 as a mechanoresponsive transcription factor that is activated by biomechanical stress 8 to support cytoskeletal reorganization, VSMC migration, 9 and proliferation. 11 As such, NFAT5 may adapt the VSMC phenotype to a potential harmful environmental stress, but nevertheless, promote responses contributing to detrimental vascular remodeling processes such as hypertension-induced arterial thickening. 11 Here, we revealed that NFAT5 is not promoting, but is rather preventing, a potentially harmful accumulation of lipids in VSMCs that may contribute to the formation of complex arteriosclerotic lesions in the long run.…”

Section: Discussionmentioning

confidence: 99%

“…For further loss-of-function studies in vitro and in vivo, we utilized a CreERT2-Nfat5 fl/fl mouse model that was introduced earlier. 11 VSMCs were isolated from aortas of CreERT2-Nfat5 fl/fl mice allowing for the inducible genetic ablation of Nfat5. These cells responded similarly to the treatment with cholesterol as human VSMCs but in addition exhibited an increased expression of Acat1, Lgals3, and Cd68 (Figure 3A).…”

Section: Cholesterol Stimulation Induces Nuclear Translocation Of Nfat5 In Human and Murine Vsmcsmentioning

confidence: 99%

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Loss of Nfat5 promotes lipid accumulation in vascular smooth muscle cells

et al. 2021

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The nuclear factor of activated T‐cells 5 (NFAT5) is a transcriptional regulator of macrophage activation and T‐cell development, which controls stabilizing responses of cells to hypertonic and biomechanical stress. In this study, we detected NFAT5 in the media layer of arteries adjacent to human arteriosclerotic plaques and analyzed its role in vascular smooth muscle cells (VSMCs) known to contribute to arteriosclerosis through the uptake of lipids and transformation into foam cells. Exposure of both human and mouse VSMCs to cholesterol stimulated the nuclear translocation of NFAT5 and increased the expression of the ATP‐binding cassette transporter Abca1, required to regulate cholesterol efflux from cells. Loss of Nfat5 promoted cholesterol accumulation in these cells and inhibited the expression of genes involved in the management of oxidative stress or lipid handling, such as Sod1, Plin2, Fabp3, and Ppard. The functional relevance of these observations was subsequently investigated in mice fed a high‐fat diet upon induction of a smooth muscle cell‐specific genetic ablation of Nfat5 (Nfat5(SMC)−/−). Under these conditions, Nfat5(SMC)−/− but not Nfat5fl/fl mice developed small, focal lipid‐rich lesions in the aorta after 14 and 25 weeks, which were formed by intracellular lipid droplets deposited in the sub‐intimal VSMCs layer. While known for being activated by external stimuli, NFAT5 was found to mediate the expression of VSMC genes associated with the handling of lipids in response to a cholesterol‐rich environment. Failure of this protective function may promote the formation of lipid‐laden arterial VSMCs and pro‐atherogenic vascular responses.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Cholesterol Stimulation Induces Nuclear Translocation Of Nfat5 In Human and Murine Vsmcsmentioning

confidence: 99%

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Loss of Nfat5 promotes lipid accumulation in vascular smooth muscle cells

et al. 2021

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“…The role of NFAT5 in arterial wall remodelling was also studied by using an inducible smooth muscle cell (SMC)-specific Nfat5 knockout mouse model [ 94 ]. In cultured mouse VSMCs, loss of the Nfat5 gene inhibited the expression of gene sets involved in controlling the cell cycle, and the interaction with the extracellular matrix and cytoskeletal dynamics.…”

Section: Nfat5 Signalling In Cardiovascular Dysfunctionmentioning

confidence: 99%

“…However, proliferation of VSMCs and the thickening of the arterial wall wee inhibited during both flow-induced collateral remodelling and hypertension-mediated arterial hypertrophy. These findings identify NFAT5 as a novel molecular determinant of biomechanically induced phenotype changes in VSMCs and wall stress-induced arterial remodelling processes [ 94 ].…”

Section: Nfat5 Signalling In Cardiovascular Dysfunctionmentioning

confidence: 99%

NFAT5-Mediated Signalling Pathways in Viral Infection and Cardiovascular Dysfunction

Zhao

Aghakeshmiri

Chen

et al. 2021

IJMS

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The nuclear factor of activated T cells 5 (NFAT5) is well known for its sensitivity to cellular osmolarity changes, such as in the kidney medulla. Accumulated evidence indicates that NFAT5 is also a sensitive factor to stress signals caused by non-hypertonic stimuli such as heat shock, biomechanical stretch stress, ischaemia, infection, etc. These osmolality-related and -unrelated stimuli can induce NFAT5 upregulation, activation and nuclear accumulation, leading to its protective role against various detrimental effects. However, dysregulation of NFAT5 expression may cause pathological conditions in different tissues, leading to a variety of diseases. These protective or pathogenic effects of NFAT5 are dictated by the regulation of its target gene expression and activation of its signalling pathways. Recent studies have found a number of kinases that participate in the phosphorylation/activation of NFAT5 and related signal proteins. Thus, this review will focus on the NFAT5-mediated signal transduction pathways. As for the stimuli that upregulate NFAT5, in addition to the stresses caused by hyperosmotic and non-hyperosmotic environments, other factors such as miRNA, long non-coding RNA, epigenetic modification and viral infection also play an important role in regulating NFAT5 expression; thus, the discussion in this regard is another focus of this review. As the heart, unlike the kidneys, is not normally exposed to hypertonic environments, studies on NFAT5-mediated cardiovascular diseases are just emerging and rapidly progressing. Therefore, we have also added a review on the progress made in this field of research.

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Mechanobiology of Atherosclerosis

Wagner

2021

Vascular Mechanobiology in Physiology and Disease

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

Cited by 8 publications

References 65 publications

Loss of Nfat5 promotes lipid accumulation in vascular smooth muscle cells

Loss of Nfat5 promotes lipid accumulation in vascular smooth muscle cells

NFAT5-Mediated Signalling Pathways in Viral Infection and Cardiovascular Dysfunction

Mechanobiology of Atherosclerosis

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