Abstract 480: A Novel Role for Telomerase in Calcific Aortic Valve Disease

Abstract

Intro: Telomerase (TERT) is an enzyme best known for its telomere-extending activities on the ends of chromosomes, however, less known are the non-canonical, transcriptional and epigenetic actitivies of TERT. We sought to assess if TERT, through non-canonical activities, contributes to the progression of calcific aortic valve disease (CAVD). It has been established that overexpression of TERT in mesenchymal stem cells primes these cells to differentiate into osteoblasts. Other studies have identified non-canonical roles for TERT in inducing the transcription of genes in inflammatory and cell differentiation pathways. Methods: Using mesenchymal stem cells, primary valve interstitial cells (VICs) from control and CAVD patients, and smooth muscle cells (SMCs) from WT and TERT knockout mice, we performed in vitro biochemical assays to study the role of TERT in the calcification process. Results: Our data shows that TERT is highly expressed in CAVD valves compared to Control valves. Under osteogenic differentiation conditions Control valve interstitial cells (VICs) upregulate TERT protein levels and calcify. Inflammatory signals induce TERT expression in VICs and exacerbates calcification. Similarly, WT vascular VSMCs readily calcify in vitro, but VSMCs from TERT knockout mice do not, and TERT deletion also reduced valve calcification in LDLR/TERT double knock mice. These studies provide evidence that TERT is necessary is the osteogenic switch of a healthy to a calcifying VIC. Knocking down TERT reduces expression of the osteogenic transcription factor RUNX2 and we further provided evidence that STAT5 may help to mediate TERTs effects on osteogenic gene transcription. Conclusion: From these data we suggest that TERT is required for valve calcification by inducing the osteogenic transition of quiescent valve interstitial cells (VICs) into calcifying VICs, and that TERT and STAT5 co-regulate transcription of osteogenic genes. These results indicate that TERT is an active contributor to the calcification process of valve tissues and our futures studies will delineate the mechanisms involved.