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Kartik Balachandran1, Philippe Sucosky, Hanjoong Jo

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Elevated mechanical stretch on aortic valves (AV) may cause calcification through bone morphogenic proteins (BMPs). Inhibiting BMPs with noggin reduced AV calcification, suggesting BMPs are key drivers in stretch-induced valve disease.

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Area of Science:

  • Cardiovascular Biology
  • Biomaterials Science
  • Mechanobiology

Background:

  • Calcified aortic valves (AV) show increased bone morphogenic proteins (BMPs) and transforming growth factor-beta1 (TGF-beta1).
  • Elevated stretch on AV increases matrix remodeling enzymes and pro-inflammatory proteins.
  • The mechanism linking stretch to AV calcification remains unclear.

Purpose of the Study:

  • To investigate if elevated mechanical stretch induces AV calcification via a BMP-dependent pathway.
  • To elucidate the role of BMPs in the pathological process of AV calcification under mechanical stress.

Main Methods:

  • Porcine AV cusps were cultured in a stretch bioreactor (10% or 15% stretch).
  • Cusps were treated with osteogenic media, high phosphate, TGF-beta1, and varying concentrations of the BMP inhibitor noggin.
  • Calcification was assessed using Alizarin red and von Kossa staining; BMP expression and apoptosis were analyzed.

Main Results:

  • 15% stretch significantly increased calcification compared to 10% stretch.
  • BMP-2, BMP-4, and Runx2 expression increased with stretch magnitude.
  • Noggin dose-dependently reduced tissue calcium content and alkaline phosphatase activity, and 15% stretch increased cellular apoptosis.

Conclusions:

  • Elevated mechanical stretch promotes AV calcification through a BMP-dependent mechanism.
  • BMPs play a critical role in stretch-induced AV calcification.
  • Targeting BMPs may offer a therapeutic strategy for preventing or treating AV calcification.