TY - JOUR
T1 - Palmitoyl acyltransferase DHHC21 mediates endothelial dysfunction in systemic inflammatory response syndrome
AU - Beard, Richard S.
AU - Yang, Xiaoyuan
AU - Meegan, Jamie E.
AU - Overstreet, Jonathan W.
AU - Yang, Clement G.Y.
AU - Elliott, John A.
AU - Reynolds, Jason J.
AU - Cha, Byeong J.
AU - Pivetti, Christopher D.
AU - Mitchell, David A.
AU - Wu, Mack H.
AU - Deschenes, Robert J.
AU - Yuan, Sarah Y.
N1 - Beard, Richard S. Jr. (2016). "Palmitoyl Acyltransferase DHHC21 Mediates Endothelial Dysfunction in Systemic Inflammatory Response Syndrome". Nature Communications, 7, 12823-1 - 12823-19. http://dx.doi.org/10.1038/ncomms12823
PY - 2016/9/22
Y1 - 2016/9/22
N2 - 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 PLCβ1 palmitoylation and signalling activity, effects significantly reduced in Zdhhc21 dep/dep and rescued by DHHC21 overexpression. Likewise, overexpression of wild-type, not mutant, PLCβ1 augments barrier dysfunction. Altogether, these data suggest the involvement of DHHC21-mediated PLCβ1 palmitoylation in endothelial inflammation.
AB - 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 PLCβ1 palmitoylation and signalling activity, effects significantly reduced in Zdhhc21 dep/dep and rescued by DHHC21 overexpression. Likewise, overexpression of wild-type, not mutant, PLCβ1 augments barrier dysfunction. Altogether, these data suggest the involvement of DHHC21-mediated PLCβ1 palmitoylation in endothelial inflammation.
KW - inflammation
KW - vascular disease
UR - http://www.scopus.com/inward/record.url?scp=84988697949&partnerID=8YFLogxK
UR - https://scholarworks.boisestate.edu/brc_facpubs/26
U2 - 10.1038/ncomms12823
DO - 10.1038/ncomms12823
M3 - Article
AN - SCOPUS:84988697949
VL - 7
JO - Nature Communications
JF - Nature Communications
M1 - 12823
ER -