期刊
CIRCULATION
卷 112, 期 9, 页码 1353-1361出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.104.519025
关键词
atherosclerosis; cardiovascular diseases; ion channels; molecule biology; muscle, smooth
资金
- NHLBI NIH HHS [P01 HL73042-02, 5R01 HL 071536-8] Funding Source: Medline
- NIA NIH HHS [1R01 AG 023073-01] Funding Source: Medline
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.
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