title: Phospholipase C beta3 deficiency leads to macrophage hypersensitivity to apoptotic induction and reduction of atherosclerosis in mice.
abstract: Atherosclerosis is an inflammatory disease that is associated with monocyte recruitment and subsequent differentiation into lipid-laden macrophages at sites of arterial lesions, leading to the development of atherosclerotic plaques. PLC is a key member of signaling pathways initiated by G protein-coupled ligands in macrophages. However, the role of this enzyme in the regulation of macrophage function is not known. Here, we studied macrophages from mice lacking PLC beta2, PLC beta3, or both PLC isoforms and found that PLC beta3 is the major functional PLC beta isoform in murine macrophages. Although PLC beta3 deficiency did not affect macrophage migration, adhesion, or phagocytosis, it resulted in macrophage hypersensitivity to multiple inducers of apoptosis. PLC beta3 appeared to regulate this sensitivity via PKC-dependent upregulation of Bcl-XL. The significance of PLC beta signaling in vivo was examined using the apoE-deficient mouse model of atherosclerosis. Mice lacking both PLC beta3 and apoE exhibited fewer total macrophages and increased macrophage apoptosis in atherosclerotic lesions, as well as reduced atherosclerotic lesion size when compared with mice lacking only apoE. These results demonstrate what we believe to be a novel role for PLC activity in promoting macrophage survival in atherosclerotic plaques and identify PLC beta3 as a potential target for treatment of atherosclerosis.
authors: Program for Vascular Biology and Therapeutics and Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, USA.
authors: Zhenglong
authors: Z
authors: Wang
authors: Bei
authors: B
authors: Liu
authors: Ping
authors: P
authors: Wang
authors: Xuemei
authors: X
authors: Dong
authors: Carlos
authors: C
authors: Fernandez-Hernando
authors: Zhong
authors: Z
authors: Li
authors: Timothy
authors: T
authors: Hla
authors: Zihai
authors: Z
authors: Li
authors: Kevin
authors: K
authors: Claffey
authors: Jonathan D
authors: JD
authors: Smith
authors: Dianqing
authors: D
authors: Wu
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis / Q000235:genetics; D054799:Phospholipase C beta / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; C494812:Bcl2l1 protein, mouse; D007527:Isoenzymes; D051020:bcl-X Protein; D011493:Protein Kinase C; D054799:Phospholipase C beta; C518037:Plcb2 protein, mouse; C518040:Plcb3 protein, mouse; D019204:GTP-Binding Proteins