DNA methylation of human telomerase reverse transcriptase associated with leukocyte telomere length shortening in hyperhomocysteinemia-type hypertension in humans and in a rat model

Background: Elevated homocysteine (Hcy) levels might play a role in the development of essential hypertension (EH). Telomere dynamics provide valuable insight into the pathogenesis of age-related diseases. The contribution of Hcy to leukocyte telomere length (LTL) shortening in EH and the underlying mechanism was examined. Methods and Results: LTL (ratio of the copy number of telomere [T] repeats to that of a single [S] gene, T/S ratio) was inversely associated with age in patients with EH (n=258) and healthy controls (n=137), but significantly decreased with the Hcy level only in patients with hypertension after adjustment for age and sex. Age, hypertension and levels of Hcy and low-density lipoprotein combined contributed to LTL shortening; an increased serum folate level could reverse the Hcy effect seen on multivariate regression analysis. In addition, qPCR and methylation-specific PCR assay revealed that LTL shortening and mRNA expression and the methylation ratio of human telomerase reverse transcriptase (hTERT) were lower in patients with EH than in controls, and gradually decreased with increasing Hcy level, but not with blood pressure, in EH patients (P_trend<0.0001, 0.004 and 0.012, respectively). Furthermore, Hyperhomocysteinemia, but not hypertension, promoted telomerase reverse transcriptase DNA hypomethylation and reduced mRNA levels, which contributed to shortened LTL in the hypertension rat model. Conclusions: Elevated Hcy but not hypertension was related to hTERT DNA hypomethylation and reduced mRNA level, thus contributing to the shortening of LTL hypertension.