The Role of Telomerase Reverse Transcriptase in the Mitochondrial Protective Functions of Angiotensin-(1–7) in Diabetic CD34+ Cells

Angiotensin (Ang)-(1-7) stimulates vasoprotective functions of diabetic (DB) CD34+ hematopoietic stem/progenitor cells partly by decreasing reactive oxygen species (ROS), increasing nitric oxide (NO) levels and decreasing TGF beta 1 secretion. Telomerase reverse transcriptase (TERT) translocates to mitochondria and regulates ROS generation. Alternative splicing of TERT results in variants alpha-, beta- and alpha-beta-TERT, which may oppose functions of full-length (FL) TERT. This study tested if the protective functions of Ang-(1-7) or TGF beta 1-silencing are mediated by mitoTERT and that diabetes decreases FL-TERT expression by inducing splicing. CD34+ cells were isolated from the peripheral blood mononuclear cells of nondiabetic (ND, n = 68) or DB (n = 74) subjects. NO and mitoROS levels were evaluated by flow cytometry. TERT splice variants and mitoDNAlesions were characterized by qPCR. TRAP assay was used for telomerase activity. Decoy peptide was used to block mitochondrial translocation (mitoXTERT). TERT inhibitor or mitoXTERT prevented the effects of Ang-(1-7) on NO or mitoROS levels in DB-CD34+ cells. FL-TERT expression and telomerase activity were lower and mitoDNA-lesions were higher in DB cells compared to ND and were reversed by Ang-(1-7) or TGF beta 1-silencing. The prevalence of TERT splice variants, with predominant beta-TERT expression, was higher and the expression of FL-TERT was lower in DB cells (n = 25) compared to ND (n = 30). Ang-(1-7) or TGF beta 1-silencing decreased TERT-splicing and increased FL-TERT. Blocking of beta-splicing increased FL-TERT and protected mitoDNA in DB -cells. The findings suggest that diabetes induces TERT-splicing in CD34+ cells and that beta-TERT splice variant largely contributes to the mitoDNA oxidative damage.