Palmdelphin Deficiency Evokes NF-κB Signaling in Valvular Endothelial Cells and Aggravates Aortic Valvular Remodeling

Yingchun Han; Jichao Zhang; Zhao Yang; Wen Jian; Yuexin Zhu; Shijuan Gao; Yan Liu; Yingkai Li; Songyuan He; Congcong Zhang; Yang Li; Bin You; Jinghua Liu; Jie Du

doi:10.1016/j.jacbts.2023.06.004

Palmdelphin Deficiency Evokes NF-κB Signaling in Valvular Endothelial Cells and Aggravates Aortic Valvular Remodeling

JACC Basic Transl Sci. 2023 Aug 30;8(11):1457-1472. doi: 10.1016/j.jacbts.2023.06.004. eCollection 2023 Nov.

Authors

Yingchun Han^{1

2}, Jichao Zhang^{1

2}, Zhao Yang¹, Wen Jian¹, Yuexin Zhu^{1

2}, Shijuan Gao^{1

2}, Yan Liu^{1

2}, Yingkai Li¹, Songyuan He¹, Congcong Zhang^{1

2}, Yang Li^{1

2}, Bin You¹, Jinghua Liu¹, Jie Du^{1

2}

Affiliations

¹ Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
² Beijing Institute of Heart, Lung and Vascular Diseases, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China.

Abstract

Palmd-deficient mice of advanced age manifest increased aortic valve peak velocity, thickened aortic valve leaflets, and excessive extracellular matrix deposition, which are key features of calcific aortic valve disease. PALMD is predominantly expressed in endothelial cells of aortic valves, and PALMD-silenced valvular endothelial cells are prone to oscillatory shear stress-induced endothelial-to-mesenchymal transition. Mechanistically, PALMD is associated with TNFAIP3 interaction protein 1, a binding protein of TNFAIP3 and IKBKG in NF-κB signaling. Loss of PALMD impairs TNFAIP3-dependent deubiquitinating activity and promotes the ubiquitination of IKBKG and subsequent NF-κB activation. Adeno-associated virus-mediated PALMD overexpression ameliorates aortic valvular remodeling in mice with calcific aortic valve disease, indicating protection.

Keywords: NF-κB; calcific aortic valve disease; endothelial cell; endothelial-to-mesenchymal transition (EndMT); palmdelphin; valvular remodeling.