Homocysteine-related hTERT DNA demethylation contributes to shortened leukocyte telomere length in atherosclerosis

Aims: Leukocyte telomere length (LTL) is shortened in patients with clinical atherosclerosis (AS). Here we aimed to explore the contribution of elevated homocysteine (Hcy) level to LTL shortening in AS patients and the underlying mechanism.

Methods: Circulating leukocytes were collected from 197 patients with AS and 165 sex- and age-matched healthy subjects for LTL determination. mRNA expression or DNA methylation of human telomerase reverse transcriptase (hTERT) was determined by real-time PCR and methylation-specific PCR assay, respectively. We established a hyperhomocysteinemia (HHcy) mice model to confirm human results.

Results: Hcy was negatively correlated with LTL shortening in AS patients (r = -0.179, p = 0.015) and controls (r = -0.146, p = 0.031). Serum folate and high-sensitivity C-reactive protein levels significantly interacted with Hcy in LTL shortening. Hcy was related to hTERT mRNA downregulation and promoter demethylation, which combined was associated with LTL shortening in AS patients. Hcy-induced LTL shortening did not differ by sites of AS lesions or infarction. Similar to clinical observations, our HHcy mice model suggested that Hcy induced DNA demethylation and downregulation of mouse TERT and further contributed to LTL shortening.

Conclusions: Elevated Hcy level induced DNA demethylation of hTERT and was closely related with hTERT downregulation, which led to LTL shortening in AS. These findings provide novel insights into an epigenetic mechanism for Hcy-related AS.