Myocardin-Related Transcription Factor A Mediates OxLDL-Induced Endothelial Injury

Fang, Fei; Yang, Yuyu; Yuan, Zhibin; Gao, Yuqi; Zhou, Jiliang; Chen, Qi; Xu, Yong

doi:10.1161/circresaha.111.240655

Cited by 97 publications

(102 citation statements)

References 45 publications

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“…32 We have previously shown that MRTF-A silencing dampens the interaction between circulating leukocytes and vascular endothelium. 16 Because infiltration of innate immune cells contributes to tissue fibrosis, 33 it is likely that reduced renal fibrosis might be a secondary consequence of a skewed immune response. Additionally, MRTF-A-deficient mice were more resistant to weight gain than WT littermates on an HFD (Supplemental Figure 1), indicating that attenuated renal fibrosis in vivo might be secondary to improved metabolic profile.…”

Section: Discussionmentioning

confidence: 99%

“…16 Specific antibodies or preimmune IgGs were added to and incubated with cell lysates overnight before being absorbed by Protein A/G-plus Agarose beads (Santa Cruz Biotechnology). Precipitated immune complex was released by boiling with 13SDS electrophoresis sample buffer.…”

Section: Protein Extraction Immunoprecipitation and Western Blotmentioning

confidence: 99%

“…15 Later investigations have revealed a more versatile role for MRTF-A in a wide range of pathophysiologic events, including leukocyte adhesion, 16 fibroblast-myofibroblast transition, 17 and megakaryocyte differentiation/maturation. 18 Newly emerged evidence has suggested that MRTF-A can directly activate collagen type I transcription in cardiac and lung fibroblast cells.…”

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confidence: 99%

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Myocardin-Related Transcription Factor A Epigenetically Regulates Renal Fibrosis in Diabetic Nephropathy

Xu¹,

Qin³

et al. 2015

Journal of the American Society of Nephrology

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113

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Diabetic nephropathy (DN) is one of the most common complications associated with diabetes and characterized by renal microvascular injury along with accelerated synthesis of extracellular matrix proteins causing tubulointerstitial fibrosis. Production of type I collagen, the major component of extracellular matrix, is augmented during renal fibrosis after chronic exposure to hyperglycemia. However, the transcriptional modulator responsible for the epigenetic manipulation leading to induction of type I collagen genes is not clearly defined. We show here that tubulointerstitial fibrosis as a result of DN was diminished in myocardin-related transcription factor A (MRTF-A) -deficient mice. In cultured renal tubular epithelial cells and the kidneys of mice with DN, MRTF-A was induced by glucose and synergized with glucose to activate collagen transcription. Notably, MRTF-A silencing led to the disappearance of prominent histone modifications indicative of transcriptional activation, including acetylated histone H3K18/K27 and trimethylated histone H3K4. Detailed analysis revealed that MRTF-A recruited p300, a histone acetyltransferase, and WD repeat-containing protein 5 (WDR5), a key component of the histone H3K4 methyltransferase complex, to the collagen promoters and engaged these proteins in transcriptional activation. Estradiol suppressed collagen production by dampening the expression and binding activity of MRTF-A and interfering with the interaction between p300 and WDR5 in renal epithelial cells. Therefore, targeting the MRTF-A-associated epigenetic machinery might yield interventional strategies against DN-associated renal fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Protein Extraction Immunoprecipitation and Western Blotmentioning

confidence: 99%

mentioning

confidence: 99%

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Myocardin-Related Transcription Factor A Epigenetically Regulates Renal Fibrosis in Diabetic Nephropathy

Xu¹,

Qin³

et al. 2015

Journal of the American Society of Nephrology

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113

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“…22 Evidence is mounting that in stressed vascular endothelium, the epigenetic machinery can actively regulate transcription to modify endothelial function tailoring to the inputs by various pathological cues. [12][13][14]23,24 By means of paracrine and endocrine, these stress signals can be relayed from the endothelium to other parts of the cardiovascular system (eg, the heart) to trigger detrimental changes. In this report, we detail an epigenetically regulated pathway wherein the histone H3K4 methyltransferase SET1 activates endothelin-1 transcription in endothelial cells and contributes to the pathogenesis of cardiac hypertrophy in response to chronic Ang II treatment ( Figure 7M).…”

Section: Discussionmentioning

confidence: 99%

Histone Methyltransferase SET1 Mediates Angiotensin II–Induced Endothelin-1 Transcription and Cardiac Hypertrophy in Mice

Yang

Weng

et al. 2015

ATVB

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Objective— Endothelin-1 is a potent vasoconstrictor derived from vascular endothelium. Elevated endothelin-1 levels are observed in a host of cardiovascular pathologies including cardiomyopathy. The epigenetic mechanism responsible for endothelin-1 induction in these pathological processes remains elusive. Approach and Results— We report here that induction of endothelin-1 expression in endothelial cells by angiotensin II (Ang II) was accompanied by the accumulation of histone H3K4 trimethylation, a preeminent histone modification for transcriptional activation, on the endothelin-1 promoter. In the meantime, Ang II stimulated the expression and the occupancy of Suv, Ez, and Trithorax domain 1 (SET1), a mammalian histone H3K4 trimethyltransferase, on the endothelin-1 promoter, both in vitro and in vivo. SET1 was recruited to the endothelin-1 promoter by activating protein 1 (c-Jun/c-Fos) and synergized with activating protein 1 to activate endothelin-1 transcription in response to Ang II treatment. Knockdown of SET1 in endothelial cells blocked Ang II–induced endothelin-1 synthesis and abrogated hypertrophy of cultured cardiomyocyte. Finally, endothelial-specific depletion of SET1 in mice attenuated Ang II–induced pathological hypertrophy and cardiac fibrosis. Conclusions— Our data suggest that SET1 epigenetically activates endothelin-1 transcription in endothelial cells, thereby contributing to Ang II–induced cardiac hypertrophy. As such, screening of small-molecule compound that inhibits SET1 activity will likely offer a new therapeutic solution to the treatment of cardiomyopathy.

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“…Whole cell lysates and nuclear proteins were obtained as previously described [19] . Specific antibodies or preimmune IgGs (P.I.I.)…”

Section: Protein Extraction Immunoprecipitation and Western Blottinmentioning

confidence: 99%

Aggf1 attenuates hepatic inflammation and activation of hepatic stellate cells by repressing Ccl2 transcription

Zeng

et al. 2016

J Biomed Res

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Liver injury represents a continuum of pathophysiological processes involving a complex interplay between hepatocytes, macrophages, and hepatic stellate cells. The mechanism whereby these intercellular interactions contribute to liver injury and fibrosis is not completely understood. We report here that angiogenic factor with G patch and FHA domains 1 (Aggf1) was downregulated in the livers of cirrhotic patients compared to healthy controls and in primary hepatocytes in response to carbon tetrachloride (CCl4) stimulation. Overexpression of Aggf1 attenuated macrophage chemotaxis. Aggf1 interacted with NF-κB to block its binding to the Ccl2 gene promoter and repressed Ccl2 transcription in hepatocytes. Macrophages cultured in the conditioned media collected from Aggf1-overexpressing hepatocytes antagonized HSC activation. Taken together, our data illustrate a novel role for Aggf1 in regulating hepatic inflammation and provide insights on the development of interventional strategies against cirrhosis.

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Myocardin-Related Transcription Factor A Mediates OxLDL-Induced Endothelial Injury

Cited by 97 publications

References 45 publications

Myocardin-Related Transcription Factor A Epigenetically Regulates Renal Fibrosis in Diabetic Nephropathy

Myocardin-Related Transcription Factor A Epigenetically Regulates Renal Fibrosis in Diabetic Nephropathy

Histone Methyltransferase SET1 Mediates Angiotensin II–Induced Endothelin-1 Transcription and Cardiac Hypertrophy in Mice

Aggf1 attenuates hepatic inflammation and activation of hepatic stellate cells by repressing Ccl2 transcription

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