Statins alter smooth muscle cell accumulation and collagen content in established atheroma of watanabe heritable hyperlipidemic rabbits.
BACKGROUND
Acute coronary syndromes often result from rupture of vulnerable plaques. The collagen content of plaques probably regulates their stability. This study tested whether HMG-CoA reductase inhibitors (statins) alter interstitial collagen gene expression or matrix metalloproteinase (MMP) levels in rabbit atheroma.


RESULTS
We administered equihypocholesterolemic doses of pravastatin (a hydrophilic statin, 50 mg. kg(-1). d(-1), n=9), fluvastatin (a cell-permeant lipophilic statin, 20 mg. kg(-1). d(-1), n=10), or placebo (n=10) to mature Watanabe heritable hyperlipidemic rabbits for 52 weeks. The fluvastatin group achieved a much higher peak plasma concentration (23.7 micromol/L) than did the pravastatin group (1.3 micromol/L) under these conditions. Immunohistochemistry revealed that MMP-1, MMP-3, and MMP-9 expression by macrophages in the intima was lower in both the pravastatin and fluvastatin groups than in the placebo group, whereas there was no difference in macrophage numbers. Numbers of intimal smooth muscle cells (SMCs) (identified by immunohistochemistry) and expression of type I procollagen mRNA (detected by in situ hybridization), however, were significantly higher in the pravastatin group than in the fluvastatin group. Treatment with pravastatin, but not fluvastatin, preserved interstitial collagen content in vivo (detected by picrosirius red polarization). In vitro, fluvastatin, but not pravastatin, decreased numbers of rabbit and human aortic SMCs without altering procollagen I mRNA expression.


CONCLUSIONS
This study showed that statins can reduce MMP expression in atheroma and that cell-permeant statins can decrease SMC number and collagen gene expression in vivo.
Fukumoto
Y
Y
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Libby
P
P
Rabkin
E
E
Hill
C C
CC
Enomoto
M
M
Hirouchi
Y
Y
Shiomi
M
M
Aikawa
M
M
D000818:Animals; D001161:Arteriosclerosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D001391:Azo Compounds; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D004396:Coloring Agents; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage; D000077340:Fluvastatin; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D006949:Hyperlipidemias / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D007150:Immunohistochemistry; D007211:Indoles / Q000008:administration & dosage; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017035:Pravastatin / Q000008:administration & dosage; D011347:Procollagen / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011817:Rabbits
D001391:Azo Compounds; D004396:Coloring Agents; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008055:Lipids; D011347:Procollagen; D012333:RNA, Messenger; C009798:C.I. direct red 80; D000077340:Fluvastatin; D003094:Collagen; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1; D017035:Pravastatin