title: Simvastatin enhances myocardial angiogenesis induced by vascular endothelial growth factor gene transfer.
abstract: 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.
authors.affiliation: Department of Cardiology, Clinical Research Center, Huddinge, Karolinska Institute, Karolinska University Hospital, 141 86 Stockholm, Sweden.
authors.forename: A J
authors.initials: AJ
authors.lastname: Siddiqui
authors.forename: T
authors.initials: T
authors.lastname: Gustafsson
authors.forename: H
authors.initials: H
authors.lastname: Fischer
authors.forename: U
authors.initials: U
authors.lastname: Widegren
authors.forename: X
authors.initials: X
authors.lastname: Hao
authors.forename: A
authors.initials: A
authors.lastname: Mansson-Broberg
authors.forename: K H
authors.initials: KH
authors.lastname: Grinnemo
authors.forename: G
authors.initials: G
authors.lastname: Dellgren
authors.forename: C
authors.initials: C
authors.lastname: Sylvén
mesh_terms: 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
chemical_list: 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