51. Lysophosphatidylcholine in phospholipase A(2)-modified LDL triggers secretion of angiopoietin 2
- Author
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Emilia A. Korhonen, Laura Hakanpaa, Kari Alitalo, Mikko I. Mäyränpää, Su Duy Nguyen, Petri T. Kovanen, Katariina Öörni, Pipsa Saharinen, Martina B. Lorey, Staff Services, Medicum, Helsinki Institute of Life Science HiLIFE, HUSLAB, Department of Pathology, Department of Biochemistry and Developmental Biology, Research Programs Unit, Pipsa Ilona Saharinen / Principal Investigator, CAN-PRO - Translational Cancer Medicine Program, Translational Cancer Biology (TCB) Research Programme, Kari Alitalo / Principal Investigator, Molecular and Integrative Biosciences Research Programme, and Biosciences
- Subjects
0301 basic medicine ,VON-WILLEBRAND-FACTOR ,030204 cardiovascular system & hematology ,Vascular biology ,Exocytosis ,LDL ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endothelial cell ,FACTOR RELEASE ,SELECTIN EXPRESSION ,Weibel–Palade body ,WEIBEL-PALADE BODIES ,Secretion ,PLASMA-LEVELS ,ATHEROSCLEROTIC PLAQUES ,Phospholipase A ,Phospholipase C ,Angiopoietin 2 ,HUMAN-ENDOTHELIAL-CELLS ,respiratory system ,PROTEIN-KINASE ,Atherosclerosis ,Lipids ,Cell biology ,Endothelial stem cell ,PROGNOSTIC VALUE ,030104 developmental biology ,Lysophosphatidylcholine ,Cholesterol ,chemistry ,CORONARY-ARTERY-DISEASE ,lipids (amino acids, peptides, and proteins) ,3111 Biomedicine ,Cardiology and Cardiovascular Medicine ,Phospholipase A(2) ,Ex vivo - Abstract
Background and aims: Secretory phospholipase A(2) (PLA(2)) hydrolyzes LDL phospholipids generating modified LDL particles (PLA(2)-LDL) with increased atherogenic properties. Exocytosis of Weibel-Palade bodies (WPB) releases angiopoietin 2 (Ang2) and externalizes P-selectin, which both play important roles in vascular inflammation. Here, we investigated the effects of PLA(2)-LDL on exocytosis of WPBs. Methods: Human coronary artery endothelial cells (HCAECs) were stimulated with PLA(2)-LDL, and its uptake and effect on Ang2 release, leukocyte adhesion, and intracellular calcium levels were measured. The effects of PLA(2)-LDL on Ang2 release and WPB exocytosis were measured in and ex vivo in mice. Results: Exposure of HCAECs to PLA(2)-LDL triggered Ang2 secretion and promoted leukocyte-HCAEC interaction. Lysophosphatidylcholine was identified as a critical component of PLA(2)-LDL regulating the WPB exocytosis, which was mediated by cell-surface proteoglycans, phospholipase C, intracellular calcium, and cytoskeletal remodeling. PLA(2)-LDL also induced murine endothelial WPB exocytosis in blood vessels in and ex vivo, as evidenced by secretion of Ang2 in vivo, P-selectin translocation to plasma membrane in intact endothelial cells in thoracic artery and tracheal vessels, and reduced Ang2 staining in tracheal endothelial cells. Finally, in contrast to normal human coronary arteries, in which Ang2 was present only in the endothelial layer, at sites of advanced atherosclerotic lesions, Ang2 was detected also in the intima, media, and adventitia. Conclusions: Our studies reveal PLA(2)-LDL as a potent agonist of endothelial WPB exocytosis, resulting in increased secretion of Ang2 and translocation of P-selectin. The results provide mechanistic insight into PLA(2)-LDL-dependent promotion of vascular inflammation and atherosclerosis.
- Published
- 2021