title: Carbamylated Low-Density Lipoprotein (cLDL)-Mediated Induction of Autophagy and Its Role in Endothelial Cell Injury.
abstract: Patients with chronic kidney disease (CKD) have high risk of cardiovascular complications. Plasma levels of carbamylated proteins produced by urea-derived isocyanate or thiocyanate are elevated in CKD patients and that they are significant predictors of cardiovascular events and all-cause mortality. Carbamylated LDL (cLDL) has pro-atherogenic properties and is known to affect major biological processes relevant to atherosclerosis including endothelial cell injury. The underlying mechanisms of cLDL-induced endothelial cell injury are not well understood. Although autophagy has been implicated in atherosclerosis, cLDL-mediated induction of autophagy and its role in endothelial cell injury is unknown. Our studies demonstrate that human coronary artery endothelial cells (HCAECs) respond to cLDL by specific induction of key autophagy proteins including LC3-I, beclin-1, Atg5, formation of lipid-conjugated LC3-II protein, and formation of punctate dots of autophagosome-associated LC3-II. We demonstrated that autophagy induction is an immediate response to cLDL and occurred in a dose and time-dependent manner. Inhibition of cLDL-induced autophagy by a specific siRNA to LC3 as well as by an autophagy inhibitor provided protection from cLDL-induced cell death and DNA fragmentation. Our studies demonstrate that autophagy plays an important role in cLDL-mediated endothelial cell injury and may provide one of the underlying mechanisms for the pathogenesis of cLDL-induced atherosclerosis in CKD patients.
authors.affiliation: Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America.|University of Arkansas for Medical Sciences, Department of Internal Medicine, Little Rock, Arkansas, United States of America.
authors.forename: Chhanda
authors.initials: C
authors.lastname: Bose
authors.affiliation: Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America.|University of Arkansas for Medical Sciences, Department of Internal Medicine, Little Rock, Arkansas, United States of America.
authors.forename: Sudhir V
authors.initials: SV
authors.lastname: Shah
authors.affiliation: University of Arkansas for Medical Sciences, Department of Biochemistry, Little Rock, Arkansas, United States of America.
authors.forename: Oleg K
authors.initials: OK
authors.lastname: Karaduta
authors.affiliation: Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America.|University of Arkansas for Medical Sciences, Department of Internal Medicine, Little Rock, Arkansas, United States of America.|University of Arkansas for Medical Sciences, Department of Biochemistry, Little Rock, Arkansas, United States of America.
authors.forename: Gur P
authors.identifier: http://orcid.org/0000-0002-1314-552X
authors.initials: GP
authors.lastname: Kaushal
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D050197:Atherosclerosis; D000071182:Autophagosomes; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5 / Q000378:metabolism; D000071186:Beclin-1 / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology; D003600:Cytosol / Q000378:metabolism; D053938:DNA Fragmentation; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008833:Microcirculation; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000503:physiopathology*
chemical_list: D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D008055:Lipids; D008077:Lipoproteins, LDL; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; C039916:carbamyl-LDL; C025946:3-methyladenine; D007770:L-Lactate Dehydrogenase; D000225:Adenine