Inhibition of Wdr5 Attenuates Ang-II-Induced Fibroblast-to-Myofibroblast Transition in Cardiac Fibrosis by Regulating Mdm2/P53/P21 Pathway

Abstract

Cardiac fibrosis is an important pathological process in many diseases. Wdr5 catalyzes the trimethylation of lysine K4 on histone H3. The effects of Wdr5 on the cardiac fibrosis phenotype and the activation or transformation of cardiac fibroblasts were investigated by Ang-II-infused mice by osmotic mini-pump and isolated primary neonatal rat cardiac fibroblasts. We found that the Wdr5 expression and histone H3K4me3 modification were significantly increased in Ang-II-infused mice. By stimulating primary neonatal rat cardiac fibroblasts with Ang II, we detected that the expression of Wdr5 and H3K4me3 modification were also significantly increased. Two Wdr5-specific inhibitors, and the lentivirus that transfected Sh-Wdr5, were used to treat primary mouse cardiac fibroblasts, which not only inhibited the histone methylation by Wdr5 but also significantly reduced the activation and migration ability of Ang-II-treated fibroblasts. To explore its mechanism, we found that the inhibition of Wdr5 increased the expression of P53, P21. Cut&Tag-qPCR showed that the inhibition of Wdr5 significantly reduced the enrichment of H3K4me3 in the Mdm2 promoter region. For in vivo experiments, we finally proved that the Wdr5 inhibitor OICR9429 significantly reduced Ang-II-induced cardiac fibrosis and increased the expression of P21 in cardiac fibroblasts. Inhibition of Wdr5 may mediate cardiac fibroblast cycle arrest through the Mdm2/P53/P21 pathway and alleviate cardiac fibrosis.

Age and Sex-Dependent Differences in Human Cardiac Matrix-Bound Exosomes Modulate Fibrosis through Synergistic miRNA Effects

“…Beyond our own dataset, we also suggest that this data can be used to identify downstream druggable targets for both study and therapeutic intervention that are not directly implicated in this dataset. This is due to the converging of target miRNAs on several pathways which have been implicated in fibrotic signaling, such as CD47 60 , ITGA2 61, 62 , c-Fos 63, 64 , HXK2 65, 66 , Klotho 67 , p21 68, 69 , and DNMT3a 70 . One particularly interesting connection is that the TGF-β-mediated effects of CD47 and ITGA2 appear downstream of c-Fos, which is known to be involved in AngII-mediated fibrosis 63 and can be regulated by some miRNAs to impact the onset of TGF-β-mediated fibrosis effects 64 in conjunction with AngII-mediated fibrotic signaling around p21 68 .…”

“…This is due to the converging of target miRNAs on several pathways which have been implicated in fibrotic signaling, such as CD47 60 , ITGA2 61, 62 , c-Fos 63, 64 , HXK2 65, 66 , Klotho 67 , p21 68, 69 , and DNMT3a 70 . One particularly interesting connection is that the TGF-β-mediated effects of CD47 and ITGA2 appear downstream of c-Fos, which is known to be involved in AngII-mediated fibrosis 63 and can be regulated by some miRNAs to impact the onset of TGF-β-mediated fibrosis effects 64 in conjunction with AngII-mediated fibrotic signaling around p21 68 . Additionally, the epigenetic changes implicated in fibrosis for both p21 and DNMT3A related pathways appear to be mediated by miRNAs or some other paracrine pathway 69–71 .…”

WD Repeat Domain 5 Inhibitors for Cancer Therapy: Not What You Think

“…Breast cancer [ 49 , 50 , 51 , 52 ], C/EBPα-mutant leukemias [ 17 ], MYC-driven cancers [ 53 ], pancreatic cancer [ 54 , 55 ], p53 gain-of-function mutant cancers [ 56 ], colorectal cancer [ 57 , 58 ], neuroblastoma [ 5 , 20 ], hepatocellular carcinoma [ 59 ], bladder cancer [ 60 , 61 ], rhabdoid tumors [ 62 ], multidrug-resistant cancers [ 63 ], and glioblastomas [ 64 ] are all cancer settings in which WDR5 inhibition has been proposed as a future therapy. More recently, a wide assortment of non-cancer applications have also been proposed, including improved in vitro fertilization in cattle [ 65 ], as well as treating aliments such as chronic kidney disease [ 66 ], neuropathic allodynia [ 67 ], Alzheimer’s [ 68 ], acute kidney injury [ 69 ], cardiac fibrosis [ 70 ], and atherosclerosis [ 71 ]. Clearly, if WDR5 inhibitors can live up to this potential, their impact on human health would be profound.…”

From multi-omics approaches to personalized medicine in myocardial infarction

“…These modifications can lead to changes in chromatin conformation, ultimately affecting the transcription of important genes ( 78 , 79 ). Histone methylation, particularly trimethylation of histone H3 on lysine-4 (H3K4me3), plays a crucial role in MI ( 80 ). JMJD3 demethylase was found to exacerbate cardiac fibrosis by reducing H3K27me3 at the beta-catenin promoter in activated cardiac fibroblasts, worsening cardiac fibrosis.…”