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Isolation and Characterization of Primary Rat Valve Interstitial Cells: A New Model to Study Aortic Valve Calcification
Published on: November 20, 2017
Rapamycin Decreases the Osteogenic Response in Aortic Valve Interstitial Cells Through the Stat3 Pathway
Xin-Sheng Deng1, Xianzhong Meng1, Rui Song1
1Department of Cardiothoracic Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Background:
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.
Methods:
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 of Stat3 and its associated signaling molecules, were analyzed.
Results:
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.
Conclusions:
Rapamycin inhibits TLR4-induced osteogenic responses in AVICs by activation of Stat3 through Akt. Rapamycin may alleviate inflammation-induced initiation and progression of CAVD.
Insights
Rapamycin reduces calcific aortic valve disease (CAVD) markers by activating Stat3 signaling. This drug may help treat CAVD by decreasing inflammation and osteogenic responses in aortic valve interstitial cells (AVICs).
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Translational Research
Background:
- Calcific aortic valve disease (CAVD) is an age-related condition linked to inflammation and osteogenesis.
- Reduced signal transducer and activator of transcription 3 (Stat3) activity in aortic valve interstitial cells (AVICs) correlates with increased inflammatory and osteogenic responses to Toll-like receptor 4 (TLR4) stimulation.
- Rapamycin, a clinical drug, activates Akt, which may upregulate Stat3.
Purpose of the Study:
- To investigate if rapamycin decreases TLR4-induced osteogenic responses in human AVICs by modulating Stat3 activity.
- To explore the role of Akt and Stat3 signaling in rapamycin's effect on AVICs.
Main Methods:
- AVICs were isolated from human heart transplant explants.
- Cells were treated with lipopolysaccharide (LPS), rapamycin, or both.
- Osteogenic markers (RUNX2, ALP, BMP-2), calcium deposition, and signaling pathway activation (Stat3, Akt) were analyzed.
Main Results:
- LPS treatment increased osteogenic marker expression.
- Rapamycin decreased baseline and LPS-induced osteogenic markers and calcium deposits.
- Rapamycin activated Akt and Stat3; Akt inhibition abolished Stat3 activation.
- Stat3 inhibition increased osteogenic marker expression.
Conclusions:
- Rapamycin inhibits TLR4-induced osteogenic responses in AVICs via Akt-mediated Stat3 activation.
- Rapamycin shows potential for alleviating inflammation-driven CAVD initiation and progression.
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