Interactive contribution of hyperinsulinemia, hyperglycemia, and mammalian target of rapamycin signaling to valvular interstitial cell differentiation and matrix remodeling
Diabetes and its major key determinants insulin resistance and hyperglycemia are known risk factors for calcific aortic valve disease (CAVD). The processes leading to molecular and structural alterations of the aortic valve are yet not fully understood. In previous studies, we could show that valvul...
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| Format: | Article |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2022.942430/full |
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| author | Jessica I. Selig H. Viviana Krug Caroline Küppers D. Margriet Ouwens D. Margriet Ouwens D. Margriet Ouwens Felix A. Kraft Elena Adler Sebastian J. Bauer Artur Lichtenberg Payam Akhyari Mareike Barth |
| author_facet | Jessica I. Selig H. Viviana Krug Caroline Küppers D. Margriet Ouwens D. Margriet Ouwens D. Margriet Ouwens Felix A. Kraft Elena Adler Sebastian J. Bauer Artur Lichtenberg Payam Akhyari Mareike Barth |
| author_sort | Jessica I. Selig |
| collection | DOAJ |
| description | Diabetes and its major key determinants insulin resistance and hyperglycemia are known risk factors for calcific aortic valve disease (CAVD). The processes leading to molecular and structural alterations of the aortic valve are yet not fully understood. In previous studies, we could show that valvular interstitial cells (VIC) display canonical elements of classical insulin signaling and develop insulin resistance upon hyperinsulinemia and hyperglycemia accompanied by impaired glucose metabolism. Analyses of cultured VIC and aortic valve tissue revealed extracellular matrix remodeling and degenerative processes. Since PI3K signaling through mammalian target of rapamycin (mTOR) is involved in fibrotic processes of the heart, we aim at further functional investigation of this particular Akt-downstream signaling pathway in the context of diabetes-induced CAVD. Primary cultures of VIC were treated with hyperinsulinemia and hyperglycemia. Phosphorylation of mTOR(Ser2448) was determined by Western blot analysis after acute insulin stimulus. Inhibition of mTOR phosphorylation was performed by rapamycin. Phosphorylation of mTOR complex 1 (MTORC1) downstream substrates 4E-BP1(Thr37/46) and P70S6K(Thr389), and MTORC2 downstream substrate Akt(Ser473) as well as the PDK1-dependent phosphorylation of Akt(Thr308) was investigated. Markers for extracellular matrix remodeling, cell differentiation and degenerative changes were analyzed by Western blot analysis, semi-quantitative real-time PCR and colorimetric assays. Hyperinsulinemia and hyperglycemia lead to alterations of VIC activation, differentiation and matrix remodeling as well as to an abrogation of mTOR phosphorylation. Inhibition of mTOR signaling by rapamycin leads to a general downregulation of matrix molecules, but to an upregulation of α-smooth muscle actin expression and alkaline phosphatase activity. Comparison of expression patterns upon diabetic conditions and rapamycin treatment reveal a possible regulation of particular matrix components and key degeneration markers by MTORC1 downstream signaling. The present findings broaden the understanding of mitogenic signaling pathways in VIC triggered by hyperinsulinemia and hyperglycemia, supporting the quest for developing strategies of prevention and tailored treatment of CAVD in diabetic patients. |
| first_indexed | 2024-04-13T22:20:13Z |
| format | Article |
| id | doaj.art-952065509df84226b5fa55f606829115 |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-04-13T22:20:13Z |
| publishDate | 2022-10-01 |
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| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-952065509df84226b5fa55f6068291152022-12-22T02:27:16ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2022-10-01910.3389/fcvm.2022.942430942430Interactive contribution of hyperinsulinemia, hyperglycemia, and mammalian target of rapamycin signaling to valvular interstitial cell differentiation and matrix remodelingJessica I. Selig0H. Viviana Krug1Caroline Küppers2D. Margriet Ouwens3D. Margriet Ouwens4D. Margriet Ouwens5Felix A. Kraft6Elena Adler7Sebastian J. Bauer8Artur Lichtenberg9Payam Akhyari10Mareike Barth11Department of Cardiac Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyDepartment of Cardiac Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyDepartment of Cardiac Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyInstitute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Düsseldorf, GermanyGerman Center for Diabetes Research (DZD), Munich, GermanyDepartment of Endocrinology, Ghent University Hospital, Ghent, BelgiumDepartment of Cardiac Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyDepartment of Cardiac Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyDepartment of Cardiac Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyDepartment of Cardiac Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyDepartment of Cardiac Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyDepartment of Cardiac Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyDiabetes and its major key determinants insulin resistance and hyperglycemia are known risk factors for calcific aortic valve disease (CAVD). The processes leading to molecular and structural alterations of the aortic valve are yet not fully understood. In previous studies, we could show that valvular interstitial cells (VIC) display canonical elements of classical insulin signaling and develop insulin resistance upon hyperinsulinemia and hyperglycemia accompanied by impaired glucose metabolism. Analyses of cultured VIC and aortic valve tissue revealed extracellular matrix remodeling and degenerative processes. Since PI3K signaling through mammalian target of rapamycin (mTOR) is involved in fibrotic processes of the heart, we aim at further functional investigation of this particular Akt-downstream signaling pathway in the context of diabetes-induced CAVD. Primary cultures of VIC were treated with hyperinsulinemia and hyperglycemia. Phosphorylation of mTOR(Ser2448) was determined by Western blot analysis after acute insulin stimulus. Inhibition of mTOR phosphorylation was performed by rapamycin. Phosphorylation of mTOR complex 1 (MTORC1) downstream substrates 4E-BP1(Thr37/46) and P70S6K(Thr389), and MTORC2 downstream substrate Akt(Ser473) as well as the PDK1-dependent phosphorylation of Akt(Thr308) was investigated. Markers for extracellular matrix remodeling, cell differentiation and degenerative changes were analyzed by Western blot analysis, semi-quantitative real-time PCR and colorimetric assays. Hyperinsulinemia and hyperglycemia lead to alterations of VIC activation, differentiation and matrix remodeling as well as to an abrogation of mTOR phosphorylation. Inhibition of mTOR signaling by rapamycin leads to a general downregulation of matrix molecules, but to an upregulation of α-smooth muscle actin expression and alkaline phosphatase activity. Comparison of expression patterns upon diabetic conditions and rapamycin treatment reveal a possible regulation of particular matrix components and key degeneration markers by MTORC1 downstream signaling. The present findings broaden the understanding of mitogenic signaling pathways in VIC triggered by hyperinsulinemia and hyperglycemia, supporting the quest for developing strategies of prevention and tailored treatment of CAVD in diabetic patients.https://www.frontiersin.org/articles/10.3389/fcvm.2022.942430/fullvalvular interstitial cells (VIC)calcific aortic valve disease (CAVD)rapamycininsulin resistancehyperinsulinemiahyperglycemia |
| spellingShingle | Jessica I. Selig H. Viviana Krug Caroline Küppers D. Margriet Ouwens D. Margriet Ouwens D. Margriet Ouwens Felix A. Kraft Elena Adler Sebastian J. Bauer Artur Lichtenberg Payam Akhyari Mareike Barth Interactive contribution of hyperinsulinemia, hyperglycemia, and mammalian target of rapamycin signaling to valvular interstitial cell differentiation and matrix remodeling Frontiers in Cardiovascular Medicine valvular interstitial cells (VIC) calcific aortic valve disease (CAVD) rapamycin insulin resistance hyperinsulinemia hyperglycemia |
| title | Interactive contribution of hyperinsulinemia, hyperglycemia, and mammalian target of rapamycin signaling to valvular interstitial cell differentiation and matrix remodeling |
| title_full | Interactive contribution of hyperinsulinemia, hyperglycemia, and mammalian target of rapamycin signaling to valvular interstitial cell differentiation and matrix remodeling |
| title_fullStr | Interactive contribution of hyperinsulinemia, hyperglycemia, and mammalian target of rapamycin signaling to valvular interstitial cell differentiation and matrix remodeling |
| title_full_unstemmed | Interactive contribution of hyperinsulinemia, hyperglycemia, and mammalian target of rapamycin signaling to valvular interstitial cell differentiation and matrix remodeling |
| title_short | Interactive contribution of hyperinsulinemia, hyperglycemia, and mammalian target of rapamycin signaling to valvular interstitial cell differentiation and matrix remodeling |
| title_sort | interactive contribution of hyperinsulinemia hyperglycemia and mammalian target of rapamycin signaling to valvular interstitial cell differentiation and matrix remodeling |
| topic | valvular interstitial cells (VIC) calcific aortic valve disease (CAVD) rapamycin insulin resistance hyperinsulinemia hyperglycemia |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2022.942430/full |
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