Glucocorticoid receptor expression is down-regulated by Lp(a) lipoprotein in vascular smooth muscle cells.
Glucocorticoids have been reported to protect against atherosclerosis and have been used clinically as protective therapy for restenosis after balloon angioplasty. Recently, Lp(a) lipoprotein [Lp(a)] levels have been suggested to be an independent risk factor for atherosclerosis, although its mechanisms of action are still uncertain. To clarify this atherogenic mechanism of Lp(a), we investigated the effects of Lp(a) on glucocorticoid receptor (GR) expression in human vascular smooth muscle cells (SMC). Levels of nuclear GR in SMC began to decrease after 12-h incubation with Lp(a), to 55 +/- 8% of the control value at 48 h; binding affinity did not change. Lp(a) had no effect on estrogen receptor binding in SMC. Moreover, low, very low, and high density lipoproteins had no effect on GR binding in SMC. The effects of Lp(a) on nuclear GR in rat SMC were very similar to those in human SMC; in contrast, Lp(a) did not alter GR or estrogen receptor levels in rat endothelial cells. GR messenger RNA levels in SMC decreased after 1-h treatment with Lp(a) to 23% of the control value after 12 h. Further, the antiproliferative effect of glucocorticoids on SMC was blunted by exposure to Lp(a). We conclude that Lp(a) down-regulates GR gene expression, resulting in a decreased number of GR in SMC. These findings suggest the possibility of a novel atherogenic mechanism of Lp(a) via inhibition of a protective action of glucocorticoids on SMC.
Sato
A
A
Baker Medical Research Institute, Melbourne, Australia.
Sheppard
K E
KE
Fullerton
M J
MJ
Sviridov
D D
DD
Funder
J W
JW
D000368:Aged; D000818:Animals; D001013:Aorta, Thoracic; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000737:chemistry / Q000648:ultrastructure; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D017270:Lipoprotein(a) / Q000494:pharmacology*; D008075:Lipoproteins, HDL / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008079:Lipoproteins, VLDL / Q000494:pharmacology; D008323:Mammary Arteries; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000032:analysis; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D005938:Glucocorticoids; D017270:Lipoprotein(a); D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid