Abstract 484: Telomerase Reverse Transcriptase And Signal Transducer And Activator Of Transcription 5a Mediates Osteogenesis In Calcific Aortic Valve Disease

Abstract

Cardiovascular calcification is a highly prevalent pathological process found in the vessels and valves in the elderly and patients with diabetes, hypertension, and renal disease. Calcific aortic valve disease (CAVD) stiffens and remodels the valve leaflets and leads to valve dysfunction, cardiac failure, and increased stroke risk. Vascular calcification can occur in the necrotic core of atherosclerotic plaques or in the medial layer of arteries. However, the initial steps dictating the onset of calcification remain ill-defined. Multiple studies have revealed that the protein telomerase reverse transcriptase (TERT), the catalytic subunit of the enzymatic complex required for telomere length maintenance, is a co-factor to stimulate gene transcription, and its overexpression primes mesenchymal stem cells to differentiate into osteoblasts. We determined that TERT is required for the calcification valve interstitial cells (VICs) and coronary smooth muscle cells (SMCs); TERT expression and protein are increased in calcified tissues and cell lines, independent of changes in telomere length. Genetic deletion of Tert in murine VICs and SMCs prevented calcification. Upon osteogenic stimulation, TERT binds to Signal Transducer and Activator of Transcription 5A/B (STAT5) to translocate into the nucleus where the complex binds to the RUNX2 promoter to induce expression. We found that VICs cultured under inflammatory conditions calcified and upregulated STAT5, suggesting that inflammatory signaling may promote calcification in VICs. Lastly, testing several STAT5 inhibitors, we determined that STAT5A is required for the calcification of VICs and SMCs. These findings are the first to suggest that TERT and STAT5 are involved in driving the osteogenic switch and calcification of vascular cells and constitute potential therapeutic targets for the treatment of CAVD.