Reciprocal regulation of endothelial-mesenchymal transition by MAPK7 and EZH2 in intimal hyperplasia and coronary artery disease

Author(s)

Vanchin, Byambasuren ^{[1, 2]} ; Sol, Marloes ^[1] ; Gjaltema, Rutger A. F. ^[1] ; Brinker, Marja ^[1] ; Kiers, Bianca ^[3] ; Pereira, Alexandre C. ^[3] ; Harmsen, Martin C. ^[1] ; Moonen, Jan-Renier A. J. ^{[1, 4]} ; Krenning, Guido ^[1]

Affiliation

^[1] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, Lab Cardiovasc Regenerat Med, NL-9713 GZ Groningen - Netherlands

^[2] Mongolian Natl Univ Med Sci, Sch Med, Dept Cardiol, Jamyan St 3, Ulaanbaatar 14210 - Mongolia

^[3] Univ Sao Paulo, Heart Inst InCor, Lab Genet & Mol Cardiol LIM13, Ave Dr Eneas C Aguiar 44, BR-05403000 Sao Paulo, SP - Brazil

^[4] Univ Groningen, Univ Med Ctr Groningen, Beatrix Childrens Hosp, Ctr Congenital Heart Dis, Dept Pediat Cardiol, Hanzepl 1 CA40, NL-9713 GZ Groningen - Netherlands

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 11, n. 1 SEP 7 2021.
• Web of Science Citations: 0

Abstract

Endothelial-mesenchymal transition (EndMT) is a form of endothelial dysfunction wherein endothelial cells acquire a mesenchymal phenotype and lose endothelial functions, which contributes to the pathogenesis of intimal hyperplasia and atherosclerosis. The mitogen activated protein kinase 7 (MAPK7) inhibits EndMT and decreases the expression of the histone methyltransferase Enhancer-of-Zeste homologue 2 (EZH2), thereby maintaining endothelial quiescence. EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 that methylates lysine 27 on histone 3 (H3K27me3). It is elusive how the crosstalk between MAPK7 and EZH2 is regulated in the endothelium and if the balance between MAPK7 and EZH2 is disturbed in vascular disease. In human coronary artery disease, we assessed the expression levels of MAPK7 and EZH2 and found that with increasing intima/media thickness ratio, MAPK7 expression decreased, whereas EZH2 expression increased. In vitro, MAPK7 activation decreased EZH2 expression, whereas endothelial cells deficient of EZH2 had increased MAPK7 activity. MAPK7 activation results in increased expression of microRNA (miR)-101, a repressor of EZH2. This loss of EZH2 in turn results in the increased expression of the miR-200 family, culminating in decreased expression of the dual-specificity phosphatases 1 and 6 who may repress MAPK7 activity. Transfection of endothelial cells with miR-200 family members decreased the endothelial sensitivity to TGF beta 1-induced EndMT. In endothelial cells there is reciprocity between MAPK7 signaling and EZH2 expression and disturbances in this reciprocal signaling associate with the induction of EndMT and severity of human coronary artery disease. (AU)

• FAPESP's process: 12/11871-0 - Correlation of histologic features of atherosclerotic plaques with coronary risk factors and the presence of biomarkers
• Grantee: Bianca Kiers
• Support Opportunities: Scholarships in Brazil - Master