Decreased plasma soluble RAGE in patients with hypercholesterolemia: effects of statins.
The receptor for advanced glycation endproducts (RAGE) is overexpressed at sites of vascular pathology. A soluble RAGE isoform (sRAGE) neutralizes the ligand-mediated damage by acting as a decoy. We hypothesized that in hypercholesterolemia up-regulation of the ligand-RAGE axis may bridge impairment of nitric oxide biosynthesis with oxidative stress. We measured in 60 hypercholesterolemic patients and 20 controls plasma total sRAGE levels, urinary 8-iso-prostaglandin (PG) F(2alpha) excretion, and plasma levels of asymmetric dimethylarginine (ADMA). The effects of two structurally different statins (pravastatin and atorvastatin) on these parameters were analyzed in 20 hypercholesterolemic subjects free of vascular disease. Plasma sRAGE was significantly lower, ADMA and urinary 8-iso-PGF(2alpha) were higher, in hypercholesterolemic versus normocholesterolemic patients. Patients on statin treatment with previous myocardial infarction had lower 8-iso-PGF(2alpha), higher sRAGE, and unchanged ADMA levels compared to subjects free of vascular disease. On multivariate regression analysis only 8-iso-PGF(2alpha) and ADMA predicted sRAGE levels. An 8-week treatment with either statin was associated with a significant reduction in urinary 8-iso-PGF(2alpha), whereas only atorvastatin raised sRAGE levels near to normal values, with no change in ADMA levels. sRAGE might serve as an endogenous protecting factor for accelerated atherosclerosis mediated by oxidative stress and endothelial dysfunction in hypercholesterolemia.
Santilli
Francesca
F
Center of Excellence on Aging, Department of Medicine, and Department of Drug Sciences, University of Chieti G. d'Annunzio Schools of Medicine and Pharmacy, 66013 Chieti, Italy.
Bucciarelli
Loredana
L
Noto
Davide
D
Cefalù
Angelo B
AB
Davì
Valentina
V
Ferrante
Elisabetta
E
Pettinella
Caterina
C
Averna
Maurizio R
MR
Ciabattoni
Giovanni
G
Davì
Giovanni
G
D000924:Anticholesteremic Agents / Q000097:blood / Q000627:therapeutic use; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy; D000069059:Atorvastatin; D003430:Cross-Sectional Studies; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine; D004311:Double-Blind Method; D005260:Female; D006538:Heptanoic Acids / Q000097:blood / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000097:blood* / Q000188:drug therapy* / Q000652:urine; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D017035:Pravastatin / Q000097:blood / Q000627:therapeutic use*; D011758:Pyrroles / Q000097:blood / Q000627:therapeutic use*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood*
D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C487735:dimethylarginine; C075750:8-epi-prostaglandin F2alpha; D009569:Nitric Oxide; D001120:Arginine; D000069059:Atorvastatin; D015237:Dinoprost; D019001:Nitric Oxide Synthase; D017035:Pravastatin