Faculty Collaboration Database

The role of telomerase reverse transcriptase in the mitochondrial protective functions of Angiotensin-(1-7) in diabetic CD34⁺ cells. Biochem Pharmacol 2024 Apr;222:116109

Date

03/09/2024

Pubmed ID

38458330

Pubmed Central ID

PMC11007670

DOI

10.1016/j.bcp.2024.116109

Scopus ID

2-s2.0-85187326117 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

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 TGFβ1 secretion. Telomerase reverse transcriptase (TERT) translocates to mitochondria and regulates ROS generation. Alternative splicing of TERT results in variants α-, β- and α-β-TERT, which may oppose functions of full-length (FL) TERT. This study tested if the protective functions of Ang-(1-7) or TGFβ1-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 mitoDNA-lesions 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 TGFβ1-silencing. The prevalence of TERT splice variants, with predominant β-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 TGFβ1-silencing decreased TERT-splicing and increased FL-TERT. Blocking of β-splicing increased FL-TERT and protected mitoDNA in DB-cells. The findings suggest that diabetes induces TERT-splicing in CD34⁺ cells and that β-TERT splice variant largely contributes to the mitoDNA oxidative damage.

Author List

Jahan J, Joshi S, Oca IM, Toelle A, Lopez-Yang C, Chacon CV, Beyer AM, Garcia CA, Jarajapu YP

Author

Andreas M. Beyer PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Angiotensin I
Diabetes Mellitus
Humans
Leukocytes, Mononuclear
Mitochondria
Peptide Fragments
Reactive Oxygen Species
Telomerase