Pravastatin increases the expression of the tissue inhibitor of matrix metalloproteinase-1 and the oncogene Bax in human aortic abdominal aneurysms.
The effect of pravastatin on matrix metalloproteinase-9 (MMP-9) and the level of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 was studied in explants of human abdominal aortic aneurysm (AAA) obtained from 13 patients. The effect of pravastatin on the apoptotic status of human AAA explants was also examined. Total MMP-9 content did not differ in human AAA explants incubated in vitro in the presence or absence of pravastatin (10-6 mol/L) for 48 h. TIMP-1 levels were significantly increased in pravastatin-incubated AAA explants, but TIMP-2 production was not modified by pravastatin. Western blot experiments showed that, whereas Bax expression was increased in pravastatin-incubated AAA explants, the expression of Bcl-2 was not modified. On the other hand, the ratio of the expression of Bax to Bcl-2, an apoptotic index, was not modified by pravastatin. In the human AAA explants, the increase in Bax expression, but not the increase in TIMP-1 expression elicited by pravastatin, was reversed by L-mevalonate, a downstream HMG-CoA reductase metabolite, suggesting that the expression of Bax and TIMP-1 followed HMG-CoA reductase-dependent and -independent pathways, respectively. In conclusion, pravastatin increases both TIMP-1 and Bax expression in human AAA explants without changes in either MMP-9 activity or the apoptotic status.
Mateos-Cáceres
Petra J
PJ
Cardiovascular Research Unit, Cardiovascular Institute, Hospital Clínico San Carlos, Madrid 28040, Spain.
López-Farré
Antonio J
AJ
Morata
Pilar C
PC
Ramos-Mozo
Priscila
P
Macaya
Carlos
C
Serrano
Francisco J
FJ
Moñux
Guillermo
G
D000368:Aged; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008875:Middle Aged; D017035:Pravastatin / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D013268:Stimulation, Chemical; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D019715:Tissue Inhibitor of Metalloproteinase-1; D051028:bcl-2-Associated X Protein; D019716:Tissue Inhibitor of Metalloproteinase-2; D020780:Matrix Metalloproteinase 9; D017035:Pravastatin