title: Modified high-density lipoprotein modulates aldosterone release through scavenger receptors via extra cellular signal-regulated kinase and Janus kinase-dependent pathways.
abstract: Patients with type 2 diabetes (T2D) manifest significant abnormalities in lipoprotein structure and function. The deleterious impact of oxidative and glycoxidative modifications on HDL-mediated atheroprotective, antiinflammatory, and antioxidative phenomena has been well established. However, the biological effects of modified HDL on adrenal steroidogenesis-which could reveal a pathophysiological link to the overactivity of the renin-angiotensin-aldosterone system and its adverse cardiovascular consequences often observed in T2D-are not well delineated. We studied the role of modified HDL on aldosterone release from adrenocortical carcinoma cells (NCI-H295R). In vitro modifications of native HDL were performed in the presence of glucose for glycoxidized HDL (glycoxHDL) and sodium hypochlorite for oxidized HDL. Angiotensin II (AngII)-sensitized H295R cells were treated with lipoproteins for 24 h, and supernatant was used to measure aldosterone release. Both native and modified HDL augmented the steroid release from AngII-sensitized cells, with glycoxHDL having the greatest impact. Both the modified forms of HDL induced a significant increase in scavenger receptor expression and employed protein kinase C as well as extracellular signal-regulated kinase as downstream effectors of aldosterone release. Native HDL and modified HDL required Janus kinase-2 for combating increased demand in steroidogenesis. Therefore, our data support the hypothesis that diabetes-induced modification of HDL may promote adrenocortical aldosterone secretion via different signal transduction pathways. This significant influence on multiple signaling mechanisms could be targeted for future research to implement novel therapeutic trials.
authors.affiliation: Department of Internal Medicine III, Carl Gustav Carus Medical School, Technical University of Dresden, Fetscherstraße 74, 01307 Dresden, Germany. Sarama.Saha@uniklinikum-dresden.de
authors.forename: Sarama
authors.initials: S
authors.lastname: Saha
authors.forename: Juergen
authors.initials: J
authors.lastname: Graessler
authors.forename: Peter E H
authors.initials: PE
authors.lastname: Schwarz
authors.forename: Claudia
authors.initials: C
authors.lastname: Goettsch
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.forename: Steffi
authors.initials: S
authors.lastname: Kopprasch
mesh_terms: D000311:Adrenal Glands / Q000166:cytology / Q000378:metabolism*; D000450:Aldosterone / Q000378:metabolism*; D000804:Angiotensin II / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation; D002788:Cholesterol Esters / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2; D015870:Gene Expression; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism / Q000502:physiology*; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010084:Oxidation-Reduction; D011493:Protein Kinase C / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D002788:Cholesterol Esters; D008075:Lipoproteins, HDL; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D017392:Thiobarbituric Acid Reactive Substances; D000804:Angiotensin II; D000450:Aldosterone; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases