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J. Cardiovasc. Dev. Dis. 2014, 1(3), 237-256; doi:10.3390/jcdd1030237

Cross Talk between NOTCH Signaling and Biomechanics in Human Aortic Valve Disease Pathogenesis

1
Division of Cardiology, the Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
2
Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH 45221, USA
3
TriHealth Heart Institute, Cardio-Thoracic Surgery, Good Samaritan Hospital, Cincinnati, OH 45242, USA
4
Molecular Cardiovascular Biology, the Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
*
Author to whom correspondence should be addressed.
Received: 1 October 2014 / Revised: 13 November 2014 / Accepted: 17 November 2014 / Published: 1 December 2014
(This article belongs to the Special Issue Semilunar Valve Development and Disease)
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Abstract

Aortic valve disease is a burgeoning public health problem associated with significant mortality. Loss of function mutations in NOTCH1 cause bicuspid aortic valve (BAV) and calcific aortic valve disease. Because calcific nodules manifest on the fibrosa side of the cusp in low fluidic oscillatory shear stress (OSS), elucidating pathogenesis requires approaches that consider both molecular and mechanical factors. Therefore, we examined the relationship between NOTCH loss of function (LOF) and biomechanical indices in healthy and diseased human aortic valve interstitial cells (AVICs). An orbital shaker system was used to apply cyclic OSS, which mimics the cardiac cycle and hemodynamics experienced by AVICs in vivo. NOTCH LOF blocked OSS-induced cell alignment in human umbilical vein endothelial cells (HUVECs), whereas AVICs did not align when subjected to OSS under any conditions. In healthy AVICs, OSS resulted in decreased elastin (ELN) and α-SMA (ACTA2). NOTCH LOF was associated with similar changes, but in diseased AVICs, NOTCH LOF combined with OSS was associated with increased α-SMA expression. Interestingly, AVICs showed relatively higher expression of NOTCH2 compared to NOTCH1. Biomechanical interactions between endothelial and interstitial cells involve complex NOTCH signaling that contributes to matrix homeostasis in health and disorganization in disease. View Full-Text
Keywords: mechanobiology; NOTCH; aortic valve; biomedical engineering; mechanotransduction mechanobiology; NOTCH; aortic valve; biomedical engineering; mechanotransduction
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Godby, R.C.; Munjal, C.; Opoka, A.M.; Smith, J.M.; Yutzey, K.E.; Narmoneva, D.A.; Hinton, R.B. Cross Talk between NOTCH Signaling and Biomechanics in Human Aortic Valve Disease Pathogenesis. J. Cardiovasc. Dev. Dis. 2014, 1, 237-256.

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