Inactivation of monocarboxylate transporter MCT3 by DNA methylation in atherosclerosis.

Abstract:

BACKGROUND:Monocarboxylate transporters (MCTs) mediate lactate transport across the plasma membrane of cells. The molecular mechanisms regulating monocarboxylate transport in smooth muscle cells (SMCs) remain poorly characterized. The aim of this study was to investigate the effects of DNA methylation on MCT expression and lactate transport in SMCs in relation to atherosclerosis. METHODS AND RESULTS:MCT expression was determined by real-time reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry in SMCs isolated from human aortas and coronary arteries. Bisulfite sequencing and confocal microscopic analysis were used to study DNA methylation and lactate transport in SMCs, respectively. Downregulation of MCT3 and impaired lactate transport were detected in proliferating/synthetic SMCs, relative to the contractile phenotype. A passage number- and atherosclerotic lesion-dependent methylation pattern of MCT3 was demonstrated in the CpG island located in exon 2. Treatment of SMCs with the demethylating agent 5-aza-2'-deoxycytidine restored MCT3 expression and normalized lactate transport. Furthermore, small interfering RNA-mediated specific MCT3 knockdown substantially stimulated SMC proliferation. CONCLUSIONS:These data indicate that DNA methylation may modify monocarboxylate transport by suppressing MCT3 expression, which could be important in regulating SMC function and the development of atherosclerosis.

journal_name

Circulation

journal_title

Circulation

authors

Zhu S,Goldschmidt-Clermont PJ,Dong C

doi

10.1161/CIRCULATIONAHA.104.519025

subject

Has Abstract

pub_date

2005-08-30 00:00:00

pages

1353-61

issue

9

eissn

0009-7322

issn

1524-4539

pii

CIRCULATIONAHA.104.519025

journal_volume

112

pub_type

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