Differential BMP Signaling Mediates the Interplay Between Genetics and Leaflet Numbers in Aortic Valve Calcification

Jae-Joon Jung; Azmi A Ahmad; Saranya Rajendran; Linyan Wei; Jiasheng Zhang; Jakub Toczek; Lei Nie; Gunjan Kukreja; Mani Salarian; Kiran Gona; Mean Ghim; Raja Chakraborty; Kathleen A Martin; George Tellides; Donald Heistad; Mehran M Sadeghi

doi:10.1016/j.jacbts.2021.12.006

Differential BMP Signaling Mediates the Interplay Between Genetics and Leaflet Numbers in Aortic Valve Calcification

JACC Basic Transl Sci. 2022 Mar 23;7(4):333-345. doi: 10.1016/j.jacbts.2021.12.006. eCollection 2022 Apr.

Authors

Jae-Joon Jung^{1

2}, Azmi A Ahmad^{1

2}, Saranya Rajendran^{1

2}, Linyan Wei^{1

2}, Jiasheng Zhang^{1

2}, Jakub Toczek^{1

2}, Lei Nie^{1

2}, Gunjan Kukreja^{1

2}, Mani Salarian^{1

2}, Kiran Gona^{1

2}, Mean Ghim^{1

2}, Raja Chakraborty¹, Kathleen A Martin¹, George Tellides^{2

3}, Donald Heistad⁴, Mehran M Sadeghi^{1

2}

Affiliations

¹ Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut, USA.
² VA Connecticut Healthcare System, West Haven, Connecticut, USA.
³ Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, USA.
⁴ Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.

Abstract

Expression of a neuropilin-like protein, DCBLD2, is reduced in human calcific aortic valve disease (CAVD). DCBLD2-deficient mice develop bicuspid aortic valve (BAV) and CAVD, which is more severe in BAV mice compared with tricuspid littermates. In vivo and in vitro studies link this observation to up-regulated bone morphogenic protein (BMP)2 expression in the presence of DCBLD2 down-regulation, and enhanced BMP2 signaling in BAV, indicating that a combination of genetics and BAV promotes aortic valve calcification and stenosis. This pathway may be a therapeutic target to prevent CAVD progression in BAV.

Keywords: BAV, bicuspid aortic valve; BMP, bone morphogenic protein; CAVD, calcific aortic valve disease; DCBLD2, discoidin, CUB and LCCL domain containing 2; EC, endothelial cell; RT-PCR, reverse-transcription polymerase chain reaction; SMAD, homolog of Caenorhabditis elegans Sma and the Drosophila mad, mothers against decapentaplegic; TAV, tricuspid aortic valve; VIC, valvular interstitial cell; WT, wild type; aortic stenosis; aortic valve; bicuspid aortic valve; calcification; mouse models; pVIC, porcine valvular interstitial cell; siRNA, small interfering RNA.

Abstract

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