Rapamycin Decreases the Osteogenic Response in Aortic Valve Interstitial Cells Through the Stat3 Pathway

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Calcific aortic valve disease (CAVD) is an age-related and slowly progressive valvular disorder. We have previously found that the increased inflammatory and osteogenic responses to Toll-like receptor 4 (TLR4) stimulation is correlated with lower signal transducer and activator of transcription 3 (Stat3) activity in aortic valve interstitial cells (AVICs). Rapamycin, a drug used clinically, induces feedback activation of Akt. Akt in turn may upregulate Stat3. Therefore we hypothesized that rapamycin will decrease TLR4-induced osteogenic response in human AVICs through modulation of Stat3 activity. AVICs were isolated from normal valves taken from the explanted hearts of patients undergoing transplantation. Cells were treated with TLR4 ligand lipopolysaccharide (LPS) or rapamycin, or both. The osteogenic markers runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), and bone morphogenetic protein 2 (BMP-2), as well as activation ofStat3 and its associated signaling molecules, were analyzed. LPS induces the expression of RUNX2, ALP, and BMP-2. Rapamycin decreased both the baseline and LPS-induced expression of RUNX2, ALP, and BMP-2. Rapamycin also decreased calcium deposit formation. Rapamycin activated both Stat3 and Akt in AVICs. Suppression of Akt resulted in abolishment of Stat3 activation. Inhibition of Stat3 enhanced expression of RUNX2, ALP, and BMP-2 at baseline and in response to LPS. Rapamycin inhibits TLR4-induced osteogenic responses in AVICs by activation of Stat3 through Akt. Rapamycin may alleviate inflammation-induced initiation and progression of CAVD.