期刊
NATURE COMMUNICATIONS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms12823
关键词
-
资金
- National Institutes of Health [HL070752, HL126646, GM097270]
- VA Merit Review [BX000799]
Endothelial dysfunction is a hallmark of systemic inflammatory response underlying multiple organ failure. Here we report a novel function of DHHC-containing palmitoyl acyltransferases (PATs) in mediating endothelial inflammation. Pharmacological inhibition of PATs attenuates barrier leakage and leucocyte adhesion induced by endothelial junction hyperpermeability and ICAM-1 expression during inflammation. Among 11 DHHCs detected in vascular endothelium, DHHC21 is required for barrier response. Mice with DHHC21 function deficiency (Zdhhc21(dep/dep)) exhibit marked resistance to injury, characterized by reduced plasma leakage, decreased leucocyte adhesion and ameliorated lung pathology, culminating in improved survival. Endothelial cells from Zdhhc21(dep/dep) display blunted barrier dysfunction and leucocyte adhesion, whereas leucocytes from these mice did not show altered adhesiveness. Furthermore, inflammation enhances PLC beta 1 palmitoylation and signalling activity, effects significantly reduced in Zdhhc21(dep/dep) and rescued by DHHC21 overexpression. Likewise, overexpression of wild-type, not mutant, PLC beta 1 augments barrier dysfunction. Altogether, these data suggest the involvement of DHHC21-mediated PLC beta 1 palmitoylation in endothelial inflammation.
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