HMG-CoA reductase inhibitors reduce interleukin-6 synthesis in human vascular smooth muscle cells.
Interleukin-6 (IL-6) is a key molecule in chronic inflammation and has been implicated in the progression of atherosclerosis. HMG-CoA reductase inhibitors (statins) may reduce the cardiovascular risk and vulnerability of atherosclerotic plaque through nonlipid as well as lipid-lowering mechanisms, but their anti-inflammatory effects on the vascular tissue have not been fully elucidated. We investigated the effects of fluvastatin on IL-6 synthesis in human vascular smooth muscle cells (VSMCs). Addition of fluvastatin decreased IL-6 synthesis in VSMCs in a time (0-24 hours)- and dose (10(-8)-10(-5) mol/L)-dependent manner. Fluvastatin also decreased IL-6 mRNA expression in VSMCs. The effects of fluvastatin on IL-6 expression were completely reversed in the presence of mevalonate or geranylgeranyl-pyrophosphate, but not squalene. Inhibition of Rho by C3 exoenzyme or Rho kinase by Y-27632 significantly decreased IL-6 expression in VSMCs. In conclusion, fluvastatin decreases IL-6 synthesis in human VSMCs through inhibition of Rho pathway. These findings suggested that reduction of IL-6 expression by statins may partially explain their therapeutic effects in patients with coronary artery disease.
Ito
Takayuki
T
Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical School, Tochigi, Japan.
Ikeda
Uichi
U
Shimpo
Masahisa
M
Ohki
Ruri
R
Takahashi
Masafumi
M
Yamamoto
Keiji
K
Shimada
Kazuyuki
K
D036002:ADP Ribose Transferases / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001905:Botulinum Toxins / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008148:Lovastatin / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D054460:rho-Associated Kinases
D000577:Amides; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; D012333:RNA, Messenger; C108830:Y 27632; D000077340:Fluvastatin; D008148:Lovastatin; C086276:cerivastatin; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D001905:Botulinum Toxins; D017035:Pravastatin