title: Palmitoyl acyltransferase DHHC21 mediates endothelial dysfunction in systemic inflammatory response syndrome.
abstract: 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 (Zdhhc21dep/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 Zdhhc21dep/depdisplay 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 Zdhhc21dep/depand 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.
authors.affiliation: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Beard
authors.affiliation: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Meegan
authors.affiliation: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Overstreet
authors.affiliation: Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA.
authors.forename: Clement G Y
authors.initials: CG
authors.lastname: Yang
authors.affiliation: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Elliott
authors.affiliation: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Reynolds
authors.affiliation: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA.
authors.forename: Byeong J
authors.initials: BJ
authors.lastname: Cha
authors.affiliation: Department of Surgery, School of Medicine, University of California at Davis, Sacramento, California 95817, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Pivetti
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Mitchell
authors.affiliation: Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA.|James A. Haley Veterans' Hospital, Tampa, Florida 33612, USA.
authors.forename: Mack H
authors.initials: MH
authors.lastname: Wu
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Deschenes
authors.affiliation: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA.|Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA.
authors.forename: Sarah Y
authors.initials: SY
authors.lastname: Yuan