title: The role of HYAL2 in LSS-induced glycocalyx impairment and the PKA-mediated decrease in eNOS-Ser-633 phosphorylation and nitric oxide production.
abstract: Hyaluronan (HA) in the endothelial glycocalyx serves as a mechanotransducer for high-shear-stress-stimulated endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. Low shear stress (LSS) has been shown to contribute to endothelial inflammation and atherosclerosis by impairing the barrier and mechanotransduction properties of the glycocalyx. Here we focus on the possible role of hyaluronidase 2 (HYAL2) in LSS-induced glycocalyx impairment and the resulting alterations in eNOS phosphorylation and NO production in human umbilical vein endothelial cells (HUVECs). We show that LSS strongly activates HYAL2 to degrade HA in the glycocalyx. The dephosphorylation of eNOS-Ser-633 under LSS was triggered after HA degradation by hyaluronidase and prevented by repairing the glycocalyx with high-molecular weight hyaluronan. Knocking down HYAL2 in HUVECs protected against HA degradation in the glycocalyx by inhibiting the expression and activity of HYAL2 and further blocked the dephosphorylation of eNOS-Ser-633 and the decrease in NO production in response to LSS. The LSS-induced dephosphorylation of PKA was completely abrogated in HYAL2 siRNA-transfected HUVECs. The LSS-induced dephosphorylation of eNOS-Ser-633 was also reversed by the PKA activator 8-Br-cAMP. We thus suggest that LSS inhibits eNOS-Ser-633 phosphorylation and, at least partially, NO production by activating HYAL2 to degrade HA in the glycocalyx.
authors: Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210001, China.|Department of Emergency Medicine, Yijishan Hospital, Wannan Medical College, Wuhu 241001, China.
authors: Xiangquan
authors: X
authors: Kong
authors: Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210001, China.
authors: Liang
authors: L
authors: Chen
authors: Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210001, China.
authors: Peng
authors: P
authors: Ye
authors: Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210001, China.
authors: Zhimei
authors: Z
authors: Wang
authors: Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210001, China.
authors: Junjie
authors: J
authors: Zhang
authors: Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210001, China.
authors: Fei
authors: F
authors: Ye
authors: Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210001, China; chmengx@126.com.
authors: Shaoliang
authors: S
authors: Chen
mesh_terms: D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000378:metabolism; D019276:Glycocalyx / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D033081:Shear Strength; D015398:Signal Transduction; D013314:Stress, Mechanical
chemical_list: D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D017868:Cyclic AMP-Dependent Protein Kinases; C473096:Hyal2 protein, human; D006821:Hyaluronoglucosaminidase