title: Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2.
abstract: Endothelial injury and dysfunction (ED) represent a link between cardiovascular risk factors promoting hypertension and atherosclerosis, the leading cause of death in Western populations. High-density lipoprotein (HDL) is considered antiatherogenic and known to prevent ED. Using HDL from children and adults with chronic kidney dysfunction (HDL(CKD)), a population with high cardiovascular risk, we have demonstrated that HDL(CKD) in contrast to HDL(Healthy) promoted endothelial superoxide production, substantially reduced nitric oxide (NO) bioavailability, and subsequently increased arterial blood pressure (ABP). We have identified symmetric dimethylarginine (SDMA) in HDL(CKD) that causes transformation from physiological HDL into an abnormal lipoprotein inducing ED. Furthermore, we report that HDL(CKD) reduced endothelial NO availability via toll-like receptor-2 (TLR-2), leading to impaired endothelial repair, increased proinflammatory activation, and ABP. These data demonstrate how SDMA can modify the HDL particle to mimic a damage-associated molecular pattern that activates TLR-2 via a TLR-1- or TLR-6-coreceptor-independent pathway, linking abnormal HDL to innate immunity, ED, and hypertension.
authors.affiliation: Cardiovascular Center, Cardiology, University Hospital Zurich and Cardiovascular Research, Institute of Physiology, University of Zurich, Zurich, Switzerland. timo.speer@uks.eu
authors.forename: Thimoteus
authors.initials: T
authors.lastname: Speer
authors.forename: Lucia
authors.initials: L
authors.lastname: Rohrer
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Blyszczuk
authors.forename: Rukshana
authors.initials: R
authors.lastname: Shroff
authors.forename: Kira
authors.initials: K
authors.lastname: Kuschnerus
authors.forename: Nicolle
authors.initials: N
authors.lastname: Kränkel
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kania
authors.forename: Stephen
authors.initials: S
authors.lastname: Zewinger
authors.forename: Alexander
authors.initials: A
authors.lastname: Akhmedov
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.forename: Tina
authors.initials: T
authors.lastname: Martin
authors.forename: Damir
authors.initials: D
authors.lastname: Perisa
authors.forename: Stephan
authors.initials: S
authors.lastname: Winnik
authors.forename: Maja F
authors.initials: MF
authors.lastname: Müller
authors.forename: Urban
authors.initials: U
authors.lastname: Sester
authors.forename: Gabriel
authors.initials: G
authors.lastname: Wernicke
authors.forename: Andreas
authors.initials: A
authors.lastname: Jung
authors.forename: Ursula
authors.initials: U
authors.lastname: Gutteck
authors.forename: Urs
authors.initials: U
authors.lastname: Eriksson
authors.forename: Jürgen
authors.initials: J
authors.lastname: Geisel
authors.forename: John
authors.initials: J
authors.lastname: Deanfield
authors.forename: Arnold
authors.initials: A
authors.lastname: von Eckardstein
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Danilo
authors.initials: D
authors.lastname: Fliser
authors.forename: Ferdinand H
authors.initials: FH
authors.lastname: Bahlmann
authors.forename: Ulf
authors.initials: U
authors.lastname: Landmesser
mesh_terms: D000328:Adult; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000737:chemistry; D062186:Arterial Pressure; D050197:Atherosclerosis / Q000276:immunology*; D002648:Child; D004727:Endothelium; D006801:Humans; D006973:Hypertension / Q000276:immunology*; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D007674:Kidney Diseases / Q000276:immunology*; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing
chemical_list: D018836:Inflammation Mediators; D008075:Lipoproteins, HDL; D051195:Toll-Like Receptor 2; C487735:dimethylarginine; D013481:Superoxides; D009569:Nitric Oxide; D001120:Arginine