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Author Notes:

Corresponding author: Hanjoong Jo, PhD, John and Jan Portman Professor, Wallace H. Coulter Department of Biomedical Engineering, Department of Medicine, The Division of Cardiology, Emory University and Georgia Institute of Technology, 1760 Haygood Drive, Atlanta, GA 30322, hjo@emory.edu

Acknowledgments: We acknowledge the many helpful discussions with Jack Heath and Philip Sucosky.

HJ is John and Jan Portman Professor and acknowledges the generous support of the late Mr. Portman for the endowed Professorship.

Disclosures: None.


Research Funding:

This work was supported by funding from the National Institutes of Health grants HL119798 and HL095070, and HL113451 to HJ.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Hematology
  • Peripheral Vascular Disease
  • Cardiovascular System & Cardiology
  • aortic valve
  • aortic valve stenosis
  • endothelial cells
  • endothelial-to-mesenchymal transition
  • inflammation
  • microRNAs
  • ubiquitination

Disturbed Flow Increases UBE2C (Ubiquitin E2 Ligase C) via Loss of miR-483-3p, Inducing Aortic Valve Calcification by the pVHL (von Hippel-Lindau Protein) and HIF-1 (Hypoxia-Inducible Factor-1) Pathway in Endothelial Cells

Journal Title:

Arteriosclerosis, Thrombosis, and Vascular Biology


Volume 39, Number 3


, Pages 467-481

Type of Work:

Article | Post-print: After Peer Review


Objective - Calcific aortic valve (AV) disease, characterized by AV sclerosis and calcification, is a major cause of death in the aging population; however, there are no effective medical therapies other than valve replacement. AV calcification preferentially occurs on the fibrosa side, exposed to disturbed flow (d-flow), whereas the ventricularis side exposed to predominantly stable flow remains protected by unclear mechanisms. Here, we tested the role of novel flow-sensitive UBE2C (ubiquitin E2 ligase C) and microRNA-483-3p (miR-483) in flow-dependent AV endothelial function and AV calcification. Approach and Results - Human AV endothelial cells and fresh porcine AV leaflets were exposed to stable flow or d-flow. We found that UBE2C was upregulated by d-flow in human AV endothelial cells in the miR-483-dependent manner. UBE2C mediated OS-induced endothelial inflammation and endothelial-mesenchymal transition by increasing the HIF-1α (hypoxia-inducible factor-1α) level. UBE2C increased HIF-1α by ubiquitinating and degrading its upstream regulator pVHL (von Hippel-Lindau protein). These in vitro findings were corroborated by immunostaining studies using diseased human AV leaflets. In addition, we found that reduction of miR-483 by d-flow led to increased UBE2C expression in human AV endothelial cells. The miR-483 mimic protected against endothelial inflammation and endothelial-mesenchymal transition in human AV endothelial cells and calcification of porcine AV leaflets by downregulating UBE2C. Moreover, treatment with the HIF-1α inhibitor (PX478) significantly reduced porcine AV calcification in static and d-flow conditions. Conclusions - These results suggest that miR-483 and UBE2C and pVHL are novel flow-sensitive anti- and pro-calcific AV disease molecules, respectively, that regulate the HIF-1α pathway in AV. The miR-483 mimic and HIF-1α pathway inhibitors may serve as potential therapeutics of calcific AV disease.

Copyright information:

© 2019 American Heart Association, Inc.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/).
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