Modulation of adrenal aldosterone release by oxidative modification of low-density lipoprotein.
BACKGROUND
Serum aldosterone is a causative factor for various metabolic and cardiovascular disorders. Low-density lipoprotein (LDL) is a major cholesterol source for aldosterone steroidogenesis; however, the effect of oxidative modification of LDL on aldosterone release is not known. We studied the effect of hypochlorite-oxidized LDL (oxLDL) on adrenal aldosterone secretion.


METHODS
LDL (native LDL (natLDL)) was obtained from healthy volunteers and oxidatively modified in vitro. NCI-H295R cells were stimulated with natLDL and oxLDL, and the aldosterone release was quantified by radioimmunoassay. Molecular changes were studied with western blot analysis and quantitative RT-PCR analysis.


RESULTS
NatLDL and oxLDL caused dose-dependent increase in aldosterone release up to threefold. However, the stimulatory effects of modified LDL on aldosterone secretion decreased with increasing degree of LDL oxidation. 24-h incubations with natLDL, mild- and medium-oxidized LDL sensitized the adrenocortical cells to subsequent angiotensin II (Ang II) stimulations by 2.9-, 2.8-, and 2.5-folds, respectively. Heavily oxidized LDL did not sensitize the cells to Ang II stimulations to a similar extent. At the molecular level, the ERK pathway was activated within a minute by both natLDL and oxLDL; however, oxLDL showed a stronger (2.75-fold at 1 and 15 min) and longer (15 min) activation of ERK than natLDL (twofold).


CONCLUSIONS
This study demonstrates the following: (i) both natLDL and hypochlorite-oxidized LDL utilize ERK pathway to mediate aldosterone release; (ii) mildly oxidized LDL sensitizes the adrenocortical cells to further stimulations by Ang II similar to natLDL that may have a role in pathological processes; (iii) extensive LDL oxidation counteracts adrenocortical aldosterone release.
Ansurudeen
Ishrath
I
Department of Internal Medicine III, University of Technology Dresden, Germany. Ishrath.Ansurudeen@ki.se
Pietzsch
Jens
J
Graessler
Juergen
J
Ehrhart-Bornstein
Monika
M
Saha
Sarama
S
Bornstein
Stefan R
SR
Kopprasch
Steffi
S
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism; D000311:Adrenal Glands / Q000187:drug effects* / Q000378:metabolism*; D000450:Aldosterone / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006997:Hypochlorous Acid / Q000737:chemistry; D008077:Lipoproteins, LDL / Q000737:chemistry* / Q000494:pharmacology*; D016877:Oxidants / Q000737:chemistry; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D011973:Receptors, LDL / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013256:Steroids / Q000096:biosynthesis; D013268:Stimulation, Chemical; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D008077:Lipoproteins, LDL; D016877:Oxidants; D011973:Receptors, LDL; D013256:Steroids; D017392:Thiobarbituric Acid Reactive Substances; C099252:oxidized low density lipoprotein; D000804:Angiotensin II; D000450:Aldosterone; D012313:RNA; D006997:Hypochlorous Acid; D048049:Extracellular Signal-Regulated MAP Kinases