Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the pathogenesis of early pulmonary arterial hypertension (PAH), pulmonary arterial adventitial fibroblast act as an initiator and mediator of inflammatory processes that predispose vessel walls to excessive vasoconstriction and pathogenic vascular remodeling. Emerging studies report that Yin Yang-1 (YY-1) plays important roles in inflammatory response and vascular injury. Our recent study finds that activation of CD40 ligand (CD40L)-CD40 signaling promotes pro-inflammatory phenotype of pulmonary adventitial fibroblasts. However, whether YY-1 is involved in CD40L-CD40 signaling-triggered inflammatory response in pulmonary adventitial fibroblasts and its underlying mechanism is still unclear. Here, we show that soluble CD40L (sCD40L) stimulation promotes YY-1 protein expression and suppresses anti-inflammatory cytokine, interleukin 10 (IL-10) expression in pulmonary adventitial fibroblasts, while YY-1 knockdown prevents sCD40L-mediated reduction of IL-10 expression via enhancing IL-10 gene transactivation. Further, we find that sCD40L stimulation significantly increases histone H3 tri-methylation at lysine 27 (H3K27me3) modification on IL-10 promoter in pulmonary adventitial fibroblasts, and YY-1 knockdown prevents the effect of sCD40L on IL-10 promoter by reducing the interaction with enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, binding to IL-10 promoter. Moreover, we find that sCD40L stimulation promotes YY-1 protein, but not messenger RNA (mRNA) expression, via decreasing N6-methyladenosine methylation on YY-1 mRNA to suppress YTHDF2-medicated mRNA decay. Overall, this in-depth study shows that the activation of CD40L-CD40 signaling upregulates YY-1 protein expression in pulmonary adventitial fibroblasts, which results in increasing YY-1 and EZH2 binding to the IL-10 promoter region to enhance H3K27me3 modification, eventually leading to suppression of IL-10 transactivation. This study first uncovers the roles of YY-1 on CD40L-CD40 signaling-triggered inflammatory response in pulmonary adventitial fibroblasts.
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PMID:Yin Yang-1 suppresses CD40 ligand-CD40 signaling-mediated anti-inflammatory cytokine interleukin-10 expression in pulmonary adventitial fibroblasts by promoting histone H3 tri-methylation at lysine 27 modification on interleukin-10 promoter. 3219 16

KL (klotho) levels decline with age, which is an important mechanistic driver of aging. KL gene deficiency is associated with hypertension. The purpose of this study is to investigate the potential role of H3K27me3 (histone 3 lysine [K] 27 trimethylation) in the regulation of KL gene expression and examine the related molecular pathways that may drive kidney cell aging. Kidneys were collected from 6-month-old WT (wild type; young WT), 30-month-old WT (aged WT), and 6- (young) and 20-month-old (aged) KL mutant mice, respectively. We demonstrated that the H3K27me3 level was increased in kidneys of aged WT and KL mutant mice versus young WT mice. Elevation of H3K27me3 levels was likely due to downregulation of the H3K27 (histone H3 Lys 27)-specific demethylase JMJD3 (the Jumonji domain containing-3) in the aged kidneys. Inhibition of PRC2 (polycomb repressive complex C2; histone trimethyltransferase) decreased the H3K27me3 levels leading to an increase in the expression of KL in cultured primary renal tubule cells assessed by Western blot and KL promoter activity assays. The chromatin immunoprecipitation qPCR assay revealed that H3K27me3 was physically associated with the KL promoter region. Furthermore, aging impaired the SGK1 (serum- and glucocorticoid-induced protein kinase 1)/FOXO3a (the forkhead box class O 3a) signaling leading to upregulation of p53 and p16 (aging markers) in the kidney of aged WT mice. KL may regulate the SGK1/FOXO3 signaling, which was decreased due to KL deficiency. Thus, aging-associated downregulation of KL gene expression may be partly attributed to upregulation of H3K27me3 levels. Downregulation of KL may impair the SGK1/FOXO3 signaling contributing to kidney cell aging.
Hypertension 2020 May
PMID:Epigenetic Regulation of KL (Klotho) via H3K27me3 (Histone 3 Lysine [K] 27 Trimethylation) in Renal Tubule Cells. 3222 80


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