JIB-04, a histone demethylase Jumonji C domain inhibitor, regulates phenotypic switching of vascular smooth muscle cells

Abstract

Background Vascular smooth muscle cell (VSMC) phenotype switching is critical for neointima formation, which is the major cause of restenosis after stenting or coronary artery bypass grafting. However, the epigenetic mechanisms regulating phenotype switching of VSMCs, especially histone methylation, are not well understood. As a main component of histone lysine demethylases, Jumonji demethylases might be involved in VSMC phenotype switching and neointima formation. Methods and results A mouse carotid injury model and VSMC proliferation model were constructed to investigate the relationship between histone methylation of H3K36 (downstream target molecule of Jumonji demethylase) and neointima formation. We found that the methylation levels of H3K36 negatively correlated with VSMC proliferation and neointima formation. Next, we revealed that JIB-04 (a pan-inhibitor of the Jumonji demethylase superfamily) could increase the methylation levels of H3K36. Furthermore, we found that JIB-04 obviously inhibited HASMC proliferation, and a cell cycle assay showed that JIB-04 caused G2/M phase arrest in HASMCs by inhibiting the phosphorylation of RB and CDC2 and promoting the phosphorylation of CHK1. Moreover, JIB-04 inhibited the expression of MMP2 to suppress the migration of HASMCs and repressed the expression of contraction-related genes. RNA sequencing analysis showed that the biological processes associated with the cell cycle and autophagy were enriched by using Gene Ontology analysis after HASMCs were treated with JIB-04. Furthermore, we demonstrated that JIB-04 impairs autophagic flux by downregulating STX17 and RAB7 expression to inhibit the fusion of autophagosomes and lysosomes. Conclusion JIB-04 suppresses the proliferation, migration, and contractile phenotype of HASMCs by inhibiting autophagic flux, which indicates that JIB-04 is a promising reagent for the treatment of neointima formation.

Galangin inhibits neointima formation induced by vascular injury via regulating the PI3K/AKT/mTOR pathway

“…The proliferation and migration of stimulated VSMCs would be accompanied by a phenotypic switching of VSMCs from a contractile to a synthetic phenotype. 17,18 To clarify the role of galangin in phenotypic switching of VSMCs, we performed immunofluorescence assays on VSMCs in different subgroups to evaluate the expressions of the phenotypic switching related marker proteins α-SMA, SM22α and OPN. The results show that galangin suppressed the PDGF-BB induced expression of OPN; however, it promoted the expressions of α-SMA and SM22α induced by PDGF-BB, as shown in Fig.…”

The epigenetic regulatory mechanisms of ferroptosis and its implications for biological processes and diseases

“…These studies on histone methylation were conducted mostly in the context of cancer and degenerative diseases, which have been shown to be closely affected by ferroptosis. Interestingly, the findings of our group and others have suggested that multiple forms of regulated cell death are involved in the development of aortic dissection (AD), and histone methylation plays a critical role in these biological processes 83,90–95 . More importantly, our recently published results revealed that ferroptosis, in particular, is involved in the development of AD 96 .…”

“…Interestingly, the findings of our group and others have suggested that multiple forms of regulated cell death are involved in the development of aortic dissection (AD), and histone methylation plays a critical role in these biological processes. 83,[90][91][92][93][94][95] More importantly, our recently published results revealed that ferroptosis, in particular, is involved in the development of AD. 96 Furthermore, by screening multiple inhibitors of methyltransferases, we found that BRD4770 negatively regulated ferroptosis in VSMCs by inhibiting the H3K9me1/2/3 modifications.…”

Elevated ENO2 Disrupts VSMCs Homeostasis Facilitating the Development of Aortic Dissection

“…Numerous studies have shown that inhibition of autophagic flux can lead to vascular injury, for example by inhibiting the proliferative migration and contractile phenotype of HAVSMCs, as well as increasing vascular senescence and calcification [48][49][50] .…”