NK-104, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, reduces osteopontin expression by rat aortic smooth muscle cells.
1. It has been suggested that osteopontin promotes the development of atherosclerosis, especially under diabetic conditions. 2. In the present study, we found that NK-104, a new potent synthetic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, reduced osteopontin expression both at protein and mRNA levels in cultured rat aortic smooth muscle cells. 3. The inhibitory effect of NK-104 was almost completely reversed by mevalonate, suggesting that mevalonate or its metabolites play important roles in the regulation of osteopontin expression. 4. Furthermore, oral administration of NK-104 (3 mg kg(-1) day(-1) for 7 days) effectively suppressed abnormally upregulated expression of osteopontin mRNA in the aorta and kidney of streptozotocin-induced diabetic rats. 5. These data support a notion that NK-104 is a suitable drug for the treatment of diabetic patients with hypercholesterolaemia.
Takemoto
M
M
Second Department of Internal Medicine, School of Medicine, Chiba University, 1-8-1 Inohana, Chiba 260-0856, Japan.
Kitahara
M
M
Yokote
K
K
Asaumi
S
S
Take
A
A
Saito
Y
Y
Mori
S
S
D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053495:Osteopontin; D011804:Quinolines / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D053495:Osteopontin; C108475:pitavastatin; D008798:Mevalonic Acid