Reciprocal Regulation Between miR-148a/152 and DNA Methyltransferase 1 Is Associated with Hyperhomocysteinemia-Accelerated Atherosclerosis

Abstract

DNA methyltransferase 1 (DNMT1) and miRNAs are both important regulators of gene expression that have been implicated in the pathogenesis of atherosclerosis. This study was designed to elucidate the potential interaction between DNMT1 and miRNAs in the context of hyperhomocysteinemia (HHcy)-related atherosclerosis. In the aorta of ApoE-/- mice fed a high methionine diet, increased expression of miR-148a/152, with decreased DNMT1 mRNA and protein levels, was detected. Similar changes were observed in cultured foam cells stimulated with homocysteine. When miR-148a/152 was overexpressed using viral vectors, DNMT1 expression was suppressed, whereas the expression of adipose differentiation-related protein (ADRP) was enhanced, and the contents of total cholesterol (TC) and cholesteryl ester (CE) were increased in cultured foam cells. Conversely, downregulation of miR-148a/152 led to elevated DNMT1 expression, reduced ADRP expression, and lowered contents of TC and CE. The luciferase reporter assay verified that DNMT1 is a target gene for miR-148a/152 and overexpression of DNMT1 can partially reverse the miR-148a/152-induced lipid accumulation in foam cells. Meanwhile, we observed that DNMT1 overexpression enhanced DNA methylation and reduced miR-148a/152 expression. Our data showed reciprocal regulation between miR-148a/152 and DNMT1 in foam cells, which likely plays a critical role in HHcy-related atherosclerosis.