Simvastatin preserves the structure of coronary adventitial vasa vasorum in experimental hypercholesterolemia independent of lipid lowering.
BACKGROUND
Previous studies have demonstrated that experimental hypercholesterolemia leads to neovascularization in the coronary artery vasa vasorum (VV). Recent evidence suggests that HMG-CoA reductase inhibitors (statins) have beneficial effects independent of lipid lowering. We aimed to determine the effect of simvastatin on coronary VV neovascularization, in the absence of cholesterol lowering.


RESULTS
Pigs were randomized to 3 groups fed a normal (N), high cholesterol (HC), or HC+simvastatin (HC+S) diet for 12 weeks. The proximal left anterior descending artery was isolated, scanned with micro-CT, and reconstructed. Quantification of the VV density in serial cross-sections along the vessel was then performed. LDL cholesterol was similarly increased in HC and HC+S compared with N. There was an increase in both VV density (4.7+/-0.3 versus 2.7+/-0.2 n/mm(2); P<0.05) and vessel wall area (3.1+/-0.2 versus 1.8+/-0.1 mm(2); P<0.05) in HC compared with N. The VV density in HC+S was preserved compared with HC (3.0+/-0.2 n/mm(2); P<0.05), despite similar increase in vessel wall area compared with N (2.5+/-0.1 mm(2); P<0.05). Coronary artery tissue expression of VEGF was increased in HC but not in HC+S compared with N. In parallel, immunoreactivity for HIF-1alpha, VEGF, MMP-2, and MMP-9 was accentuated in the outer media in HC but not in HC+S compared with N.


CONCLUSIONS
This study demonstrates that simvastatin attenuates hypoxia in the coronary artery wall and VV neovascularization in experimental hypercholesterolemia, despite no change in plasma lipids. These data are consistent with an additional mechanism for the vascular effects of the statins, independent of cholesterol lowering.
Wilson
Stephanie H
SH
Divisions of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA.
Herrmann
Joerg
J
Lerman
Lilach O
LO
Holmes
David R
DR
Napoli
Claudio
C
Ritman
Erik L
EL
Lerman
Amir
A
D000818:Animals; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood; D017023:Coronary Angiography; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D004036:Diet, Atherogenic; D016228:Endothelial Growth Factors / Q000276:immunology / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000097:blood* / Q000000981:diagnostic imaging / Q000188:drug therapy; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D008222:Lymphokines / Q000276:immunology / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000276:immunology / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D013552:Swine; D014057:Tomography, X-Ray Computed; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism; D014651:Vasa Vasorum / Q000000981:diagnostic imaging / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D002784:Cholesterol; D019821:Simvastatin; D020782:Matrix Metalloproteinases