Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease. J Mol Cell Cardiol 2013 Jul;60:27-35
Date
04/16/2013Pubmed ID
23583836Pubmed Central ID
PMC4058883DOI
10.1016/j.yjmcc.2013.04.001Scopus ID
2-s2.0-84877026320 (requires institutional sign-in at Scopus site) 127 CitationsAbstract
The mature aortic valve is composed of a structured trilaminar extracellular matrix that is interspersed with aortic valve interstitial cells (AVICs) and covered by endothelium. Dysfunction of the valvular endothelium initiates calcification of neighboring AVICs leading to calcific aortic valve disease (CAVD). The molecular mechanism by which endothelial cells communicate with AVICs and cause disease is not well understood. Using a co-culture assay, we show that endothelial cells secrete a signal to inhibit calcification of AVICs. Gain or loss of nitric oxide (NO) prevents or accelerates calcification of AVICs, respectively, suggesting that the endothelial cell-derived signal is NO. Overexpression of Notch1, which is genetically linked to human CAVD, retards the calcification of AVICs that occurs with NO inhibition. In AVICs, NO regulates the expression of Hey1, a downstream target of Notch1, and alters nuclear localization of Notch1 intracellular domain. Finally, Notch1 and NOS3 (endothelial NO synthase) display an in vivo genetic interaction critical for proper valve morphogenesis and the development of aortic valve disease. Our data suggests that endothelial cell-derived NO is a regulator of Notch1 signaling in AVICs in the development of the aortic valve and adult aortic valve disease.
Author List
Bosse K, Hans CP, Zhao N, Koenig SN, Huang N, Guggilam A, LaHaye S, Tao G, Lucchesi PA, Lincoln J, Lilly B, Garg VAuthor
Joy Lincoln PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Active Transport, Cell NucleusAnimals
Aortic Valve
Basic Helix-Loop-Helix Transcription Factors
Calcinosis
Cell Cycle Proteins
Cell Nucleus
Heart Defects, Congenital
Heart Valve Diseases
Human Umbilical Vein Endothelial Cells
Humans
Mice
Nitric Oxide
Receptor, Notch1
Repressor Proteins
Signal Transduction
Swine