Role for telomerase in pulmonary hypertension

Area of Science:

• Cardiovascular Research
• Cell Biology
• Pulmonary Medicine

Background:

• Dysregulated cell growth in pulmonary hypertension (PH) is linked to telomerase reverse transcriptase (TERT).
• TERT maintains telomere length with TERC and controls cell growth.
• This study examines lung TERT in human and experimental PH and its role in pulmonary artery smooth muscle cell (PA-SMC) proliferation.

Purpose of the Study:

• Investigate the role of TERT in pulmonary hypertension (PH).
• Determine TERT's function in pulmonary artery smooth muscle cell (PA-SMC) proliferation.
• Explore TERT as a potential therapeutic target for PH.

Main Methods:

• Assessed TERT expression and activity in human PH lungs and experimental mouse models of PH.
• Utilized TERT inhibitor (imetelstat) and activator (TA65) in cultured mouse PA-SMCs.
• Examined PH development and PA-SMC proliferation in TERC(-/-) and TERT(-/-) mice under hypoxia.
• Administered imetelstat and TA65 to mice to assess PH progression and reversal.

Main Results:

• TERT was highly expressed in PA-SMCs in human and experimental PH lungs.
• TERT inhibition reduced PA-SMC proliferation, while activation increased it.
• TERT deficiency in mice lessened PH severity and PA-SMC proliferation.
• Imetelstat treatment reduced or reversed PH in mice, decreasing TERT expression.
• TA65 treatment exacerbated PH.

Conclusions:

• Telomerase exerts telomere-independent effects on PA-SMC growth in PH.
• TERT inhibition represents a potential therapeutic strategy for PH.