Matrix modulation in degenerative aortic valve disease due to metabolically-independent insulin action?

• Applicant: Dr. Mareike Barth
• Subject Area: Cardiac and Vascular Surgery
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421961956

• Final Report Year: 2023

Final Report Abstract

Fibrotic changes are substantial during development of degenerative aortic valve disease. Diabetic disorders initiate and aggravate further pathogenesis even during moderate elevation of insulin levels independently from mechanisms regulating metabolism. Ageing, development of pre-diabetic states and cardiac pathologies represent major health care expenditures and mortality risk factors world-wide. Thus, early rebalancing, prevention and additional intervention is of vital interest in the context of individual healthcare and socioeconomic calculations. We found that even short-term hyperinsulinemia severely disturbs insulinsensitivity in interstitial cells. We therefore will identify mitogenic pathways leading to fibrotic changes associated to insulin-receptor mediated signaling. These will be new and additive targets for an early clinical intervention in pre-diabetic states. We will analyze expression and functional addressability of insulin-related downstream signaling in isolated interstitial cells from sheep aortic valves and in sheep aortic valve cusps. Translational relevance will be clarified in human aortic valve cusps from non-diabetic patients. We hypothesize that insulin leads to pathological alterations of extracellular matrix in degenerative aortic valve disease through mitogenic pathways independently from glucose metabolism.

Publications

• Crosstalk of Diabetic Conditions with Static Versus Dynamic Flow Environment—Impact on Aortic Valve Remodeling. International Journal of Molecular Sciences, 22(13), 6976.
  Selig, Jessica I.; Boulgaropoulos, Joana; Niazy, Naima; Ouwens, D. Margriet; Preuß, Karlheinz; Horn, Patrick; Westenfeld, Ralf; Lichtenberg, Artur; Akhyari, Payam & Barth, Mareike
  
• Metabolic effects on aortic valves in static and pulsatile 3D cultivation environments. – Kurzvortrag bei der 57. Jahrestagung der Europäischen Gesellschaft für Diabetesforschung (EASD) - Diabetologia 64 (Suppl 1), 1–380 (2021).
  Selig JI; Boulgaropoulos J.; Niazy N.; Ouwens DM; Preuss K.; Westenfeld R.; Lichtenberg A.; Akhyari P. & Barth M.
  
• Interactive contribution of hyperinsulinemia, hyperglycemia, and mammalian target of rapamycin signaling to valvular interstitial cell differentiation and matrix remodeling. Frontiers in Cardiovascular Medicine, 9.
  Selig, Jessica I.; Krug, H. Viviana; Küppers, Caroline; Ouwens, D. Margriet; Kraft, Felix A.; Adler, Elena; Bauer, Sebastian J.; Lichtenberg, Artur; Akhyari, Payam & Barth, Mareike
  
• Metabolism of valvular interstitial cells is glucose dependent and susceptible to different diabetic conditions. – Kurzvortrag bei der 58. Jahrestagung der Europäischen Gesellschaft für Diabetesforschung (EASD) - Diabetologia 65 (Suppl 1), 1–469 (2022).
  Barth M.; Selig JI; Krug HV; Küppers C.; Ouwens DM; Lichtenberg A. & Akhyari P.
  
• Mitogenic signalling pathways in valvular interstitial cells and their dependency from diabetic conditions. – Kurzvortrag bei der 58. Jahrestagung der Europäischen Gesellschaft für Diabetesforschung (EASD) - Diabetologia 65 (Suppl 1), 1–469 (2022).
  Selig JI; Kraft FA; Adler E.; Ouwens DM; Lichtenberg A.; Akhyari P. & Barth M.
  
• Remodeling of valvular interstitial cells under diabetic treatment is mediated by mTOR signaling. – Vortrag bei der 7. Jahrestagung der Internationalen Herzklappengesellschaft (HVS)
  Selig JI; Krug V.; Kraft FA; Adler E.; Ouwens DM; Lichtenberg A.; Akhyari P. & Barth M.