Abstract We0071: The lncRNA TERC inhibits TERT Non-Canonical Function in Cardiovascular Calcification.

Cardiovascular calcification is a complex disease highly prevalent in the aging population. Calcific aortic valve disease (CAVD) is the leading heart valve disorder. The osteogenic reprogramming of valve cells is central to this condition. However, the precise mechanism by which a valve cell transforms into an osteogenic state remains to be determined. Telomerase is a multi-subunit complex primarily known for maintaining telomere length. The core of this complex consists of the enzyme telomerase reverse transcriptase (TERT) and the long non-coding RNA component TERC ( lncTERC ). Beyond telomere maintenance, the TERT protein also promotes cell survival, regulates gene expression as a co-activator, and plays a role in cardiovascular aging and the development of atherosclerosis. lncTERC is mainly known for its role as a template for adding telomeric repeats to chromosomal ends. Emerging evidence shows that lncTERC regulates transcription and promotes inflammation. Further, lncTERC deficiency accelerates pulmonary alveolar cell senescence, differentiation, and apoptosis. We found that TERT is highly expressed in CAVD tissues and required for the osteogenic differentiation of valve cells. These findings were validated in a mouse model of diet-induced cardiovascular calcification, where Tert -/- mice exhibited impaired calcification compared to Tert +/+ mice. Mechanistically, TERT expression is induced by inflammation, and we found that TERT forms a complex with the Signal Transducer and Activator of Transcription 5 (STAT5) during osteogenic differentiation, promoting the expression of RUNX2 gene, which is critical for bone osteogenesis and the physiopathological calcification of vascular cells. Finally, we provide evidence that inhibiting TERT telomeric activity or depleting lncTERC does not affect TERT function in osteogenic reprogramming; mouse valve lncTERC -/- cells calcify show elevated calcification compared to lncTERC +/+ , while TERT -/- cells showed no calcification. Furthermore, the expression of RUNX2 was higher in lncTERC-/- cells than that observed in the lncTERC +/+ cells during osteogenic reprogramming. In conclusion, our data suggest that lncTERC inhibits TERT co-transcriptional activity and may dictate whether TERT exerts non-canonical functions. These data identify a novel mechanism and potential therapeutic target for treating vascular calcification.