Epigenetic regulation of 5-lipoxygenase in the phenotypic plasticity of valvular interstitial cells associated with aortic valve stenosis

Valvular interstitial cells (VICs) are of mesenchymal origin and may differentiate into immune-like cells. This phenotypic plasticity is a key feature of aortic valve stenosis, but the role of epigenetic mechanisms has not previously been explored. Here we compared normal and calcified human aortic valve tissue. Calcified tissue exhibited decreased DNA-methylation in the promoter of the gene encoding the proinflammatory enzyme 5-lipoxygenase (5-LO), accompanied by increased 5-LO mRNA levels. Treatment of cultured VICs with the DNA methyltransferase inhibitor: 5-Aza-2’-deoxycytidine increased 5-LO mRNA levels and leukotriene production. These findings provide a first piece of evidence for epigenetic modifications of VICs in valvular heart disease.

► A role of epigenetic regulation in aortic stenosis is proposed.
► 5-lipoxygenase promoter methylation decreased in calcified human valvular tissue.
► Hypomethylation of valvular interstitial cells (VICs) increased 5-lipoxygenase mRNA.
► Hypomethylated VICs produced increased levels of leukotrienes.
► Epigenetics may be one mechanism in phenotypic transformation of VICs.