Altered collagen homeostasis in human aortic smooth muscle cells (HAoSMCs) induced by aldosterone.
The importance of aldosterone for cardiovascular diseases is well established. Most of the adverse effects seem to originate from its ability to produce vascular injury, including fibrosis. It is currently under debate whether aldosterone per se is able to induce fibrosis or whether it acts as a cofactor under pathological conditions. We tested whether aldosterone per se and in the presence of reactive oxygen stress (H(2)O(2)) enhances collagen abundance in human aortic smooth muscle cell (HAoSMC) media in primary culture and, if so, by which means. Collagen abundance, as well as epidermal growth factor receptor (EGFR) expression and ERK1/2 phosphorylation, was investigated by ELISA and Western blot. Collagenase activity and H(2)O(2) formation were determined by fluorometry and luminometry. Aldosterone alone did not affect collagen abundance but potentiated the stimulatory effect of low concentrations of H(2)O(2) (1-10 micromol/l). This effect disappeared when shedding of membrane-bound EGFR ligands was prevented by GM6001. EGFR expression and cellular EGF responsiveness were enhanced by aldosterone. Inhibition of the EGFR kinase (tyrphostin AG1478) prevented the increase of collagen. The increase in collagen abundance was prevented by blockade of the mineralocorticoid receptor (MR) and could be reproduced by MR transfection into Chinese hamster ovary cells. We conclude that aldosterone sensitizes HAoSMC for H(2)O(2)-induced increase of collagen abundance at least in part by enhanced EGFR expression.
Gekle
Michael
M
Physiologisches Institut, Universität Würzburg, Röntgenring 9, 97070, Würzburg, Germany. michael.gekle@mail.uni-wuerzburg.de
Mildenberger
Sigrid
S
Freudinger
Ruth
R
Grossmann
Claudia
C
D000450:Aldosterone / Q000494:pharmacology*; D001483:Base Sequence; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D017364:Collagenases / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics
D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D003094:Collagen; D006861:Hydrogen Peroxide; D066246:ErbB Receptors; D017364:Collagenases; D018093:Gelatinases