Rosuvastatin inhibits TIMP-2 and promotes myocardial angiogenesis.
BACKGROUND
Angiogenesis is usually driven by inflammation. Matrix metalloproteinases MMP-3 and MMP-9 and tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2 are implicated in vascular remodeling. TIMP-2 exhibits antiangiogenic properties. Statins show benefits that are additional to lipid lowering including pro- and antiangiogenic properties. Atherosclerotic lesions in the coronary arteries have been well studied, but less is known about the fine terminal branches of the myocardial vasculature.


METHODS
To examine this, we studied rosuvastatin (RSV) treatment in ApoE knockout (ApoE(-/-)) mice fed a high cholesterol (HC) diet. Hearts from ApoE(-/-) mice on a normal diet, HC diet and HC diet with RSV were harvested to determine MMP-3, MMP-9, TIMP-1, TIMP-2, vascular endothelial growth factor (VEGF)-A and estrogen receptor-α (ER-α) mRNA.


RESULTS
RSV inhibited TIMP-1 and TIMP-2 expression and enhanced myocardial VEGF-A and ER-α expression, independently of plasma lipid level changes, but had no effect on MMP-3 and MMP-9 expression.


CONCLUSIONS
These modulations of TIMPs, VEGF and ER-α expression induced by RSV may act as local stimulating factors for arteriolar growth in the myocardium.
Department of Laboratory Medicine, Care Sciences and Society (Clinical Geriatrics), Karolinska University Hospital Huddinge and Karolinska Institute, Stockholm, Sweden.
Anwar J
AJ
Siddiqui
Thomas
T
Gustafsson
Christer
C
Sylven
Milita
M
Crisby
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D005464:Fluorobenzenes / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008055:Lipids / Q000097:blood; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D011743:Pyrimidines; D013449:Sulfonamides; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D042461:Vascular Endothelial Growth Factor A; D019716:Tissue Inhibitor of Metalloproteinase-2; D000068718:Rosuvastatin Calcium; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9