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Multifunctional Ca/calmodulin-dependent protein kinase II (CaMKII) is a multi-gene family with isoform-specific regulation of vascular smooth muscle (VSM) functions. In previous studies we found that vascular injury resulted in VSM de-differentiation and reduced expression of the CaMKIIg isoform in medial wall VSM. Smooth muscle knockout of CaMKIIg enhanced injury-induced VSM neointimal hyperplasia whereas CaMKIIg over-expression inhibited VSM proliferation and neointimal formation. In this study, we evaluated DNA cytosine methylation/demethylation as a mechanism for regulating CaMKII isoform expression in VSM. Inhibition of cytosine methylation with 5-Aza-2'-deoxycytidine, significantly up-regulated CaMKIIg expression in cultured VSM cells and inhibited CaMKIIg downregulation in organ-cultured aorta . Using methylated cytosine immuno-precipitation, the rat promoter was found hypomethylated in differentiated VSM, whereas injury- or cell culture-induced VSM de-differentiation coincided with promoter methylation and decreased expression. We report for the first time, that VSM cell phenotype switching is accompanied by marked induction of thymine DNA glycosylase (TDG) protein and mRNA expression in injured arteries and in cultured VSM synthetic phenotype cells. Silencing in VSM promoted expression of CaMKIIg and differentiation markers, including myocardin, and inhibited VSM cell proliferation and injury-induced neointima formation. This study indicates that CaMKIIg expression in VSM is regulated by cytosine methylation/demethylation and that TDG is an important determinant of this process and, more broadly, VSM phenotype switching and function.
This article was published in the following journal.
Name: American journal of physiology. Heart and circulatory physiology
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An enzyme that removes THYMINE and URACIL bases mispaired with GUANINE through hydrolysis of their N-glycosidic bond. These mispaired nucleotides generally occur through the hydrolytic DEAMINATION of 5-METHYLCYTOSINE to thymine.
A GATA transcription factor that is expressed predominately in SMOOTH MUSCLE CELLS and regulates vascular smooth muscle CELL DIFFERENTIATION.
A beta-adrenergic agonist that causes direct relaxation of uterine and vascular smooth muscle. Its vasodilating actions are greater on the arteries supplying skeletal muscle than on those supplying skin. It is used in the treatment of peripheral vascular disease and in premature labor.
The nonstriated, involuntary muscle tissue of blood vessels.
Precursor cells destined to differentiate into smooth muscle myocytes (MYOCYTES, SMOOTH MUSCLE).
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