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Remodeling Of Valvular Interstitial Cells Under Diabetic Treatment Is Mediated By MTOR Signaling
Jessica I. Selig1, Hannah Viviana Krug1, Felix Kraft1, Elena Adler1, D. Margriet Ouwens2, Artur Lichtenberg1, Payam Akhyari1, Mareike Barth1.
1Department of Cardiac Surgery, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany, 2Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Düsseldorf, Germany.

OBJECTIVE: Valvular interstitial cells (VIC) acquire impaired insulin action under hyperglycemia and hyperinsulinemia, shown by disturbed AKT/GSK3 signaling. Furthermore, diabetic treatment leads to early signs of degenerative changes of VIC. Future prevention strategies or tailored therapeutic treatment for diabetic patients with aortic valve disease warrants understanding of involved signaling pathways. Thus, the purpose of this study is to evaluate whether mitogenic pathways like mTOR signaling might mediate these degenerative changes.
METHODS: Primary cultures of ovine VIC were treated with hyperglycemia (4.5 g/L glucose) and hyperinsulinemia (100 nM insulin) for six days. Phosphorylation levels of mTORSer2448 were determined by Western blot analysis. Rapamycin was used for inhibition of mTOR phosphorylation. Markers for matrix remodeling and degenerative changes were analyzed by gene expression analysis and colorimetric assays.
RESULTS: Hyperinsulinemia significantly impairs mTORSer2448 phosphorylation, while hyperglycemia alone has no impact on mTOR signaling. Inhibition of mTOR phosphorylation by rapamycin leads to a decrease of collagen type 1, elastin and biglycan and to an increase of alpha smooth muscle actin under normoglycemia compared to untreated controls. Under rapamycin treatment, hyperinsulinemia leads to a decrease of alpha smooth muscle actin and increase in hyaluronic acid synthase 2 gene expression as well as to a lower viability of the cells.
CONCLUSIONS: Diabetic conditions affect VIC remodeling, while rapamycin significantly modulates these diabetic changes. Thus, our findings implicate a possible role for insulin-dependent mTOR signaling in diabetes-induced degenerative changes of aortic heart valves.


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