Simvastatin enhances myocardial angiogenesis induced by vascular endothelial growth factor gene transfer.
Statins have cardioprotective roles. We explored the cardiac angiogenic effects of simvastatin in combination with transient overexpression of vascular endothelial growth factor (VEGF). Compared with normal mice, 1-year-old ApoE(-/-) mice fed on a high-fat diet (HFD) had about 30% less myocardial capillary (P < 0.001) and arteriolar (P < 0.03) densities, associated with decreased VEGF (55%), VEGFR-1 (56%) and VEGFR-2 (78%) mRNA expressions and myocardial endothelial nitric oxide synthase (eNOS) production (58%). By contrast, angiopoietin-1 and angiopoietin-2 mRNA expressions were increased (500% P < 0.02, and 400% P < 0.01, respectively) in the ApoE(-/-) hearts. No change was observed in Tie-2 gene expression. Phosphorylation of antiapoptotic Akt was lower and proapoptotic p38 mitogen-activated protein kinase (MAPK) was higher in the ApoE(-/-) mice compared with controls. Intramyocardial VEGF gene transfer increased capillary and arteriolar densities in the ApoE(-/-) mice, and simvastatin treatment further enhanced capillary density (P < 0.03) to a level similar to that of normal mice. Simvastatin did not change the lipid profile but blocked p38 MAPK phosphorylation in the ApoE(-/-) myocardium. Concurrent with these changes, there were increased levels of expression of mVEGF (P < 0.04) and VEGFR-2 (P < 0.03) mRNAs and increased production of eNOS (P < 0.05) in the ApoE(-/-) mice, while no changes were detected in the angiopoietin system. Thus, increased myocardial angiogenesis in the ApoE(-/-) mice following transient overexpression of VEGF is further increased by additional simvastatin treatment. These effects occurred concurrently with simvastatin-induced stimulation of the VEGF system, increased eNOS production and reduction in p38 MAPK phosphorylation.
Siddiqui
A J
AJ
Department of Cardiology, Clinical Research Center, Huddinge, Karolinska Institute, Karolinska University Hospital, 141 86 Stockholm, Sweden.
Gustafsson
T
T
Fischer
H
H
Widegren
U
U
Hao
X
X
Mansson-Broberg
A
A
Grinnemo
K H
KH
Dellgren
G
G
Sylvén
C
C
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D003331:Coronary Vessels / Q000187:drug effects* / Q000254:growth & development; D018014:Gene Transfer Techniques; D006801:Humans; D008055:Lipids / Q000097:blood; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019821:Simvastatin / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D008055:Lipids; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D019821:Simvastatin; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases