title: Effect of combined treatment with rosuvastatin and protein kinase Cβ2 inhibitor on angiogenesis following myocardial infarction in diabetic rats.
abstract: The aim of the present study was to investigate the effects of combined treatment with rosuvastatin and LY333531, a selective protein kinase C (PKC)β2 inhibitor, on angiogenesis under hyperglycemic conditions. Human umbilical vein endothelial cells (HUVECs) cultured in medium containing a normal or high concentration of glucose (33.3 mmol/l) were treated with rosuvastatin (0.1 µmol/l) alone or in combination with LY333531 (10 nmol/l). HUVEC migration and tube formation were assessed. Furthermore, rats with streptozotocin-induced diabetes were randomly divided into groups and treated with either rosuvastatin alone (5 mg/kg/day) or in combination with LY333531 (10 mg/kg/day) for 4 weeks following the induction of myocardial infarction (MI). Echocardiographic patterns, the extent of myocardial fibrosis, capillary density in myocardial tissue, the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS), as well as the expression levels of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-α (HIF‑1α) were assessed. The results from the in vitro experiment revealed that the tube-forming and migration ability of the HUVECs exposed to high-glucose medium was significantly improved in the group treated with the combination of rosuvastatin and LY333531. In vivo, the combination of rosuvastatin and LY333531 significantly improved left ventricular function, reduced the extent of myocardial fibrosis and increased myocardial capillary density compared to treatment with rosuvastatin alone. In addition, the expression levels of VEGF, and Akt and eNOS phosphorylation were significantly higher in the group exposed to the combination treatment than in the group treated with rosuvastatin alone. The results of the present study indicate that, compared to treatment with rosuvastatin alone, combined treatment with rosuvastatin and LY333531 promotes a greater level of angiogenesis in diabetic rats with MI. This effect is likely mediated through the upregulation of the VEGF‑dependent Akt/eNOS signaling pathway.
authors.affiliation: Division of Cardiology, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai Jiaotong University School of Medicine, State Key Discipline Division, Shanghai 200233, P.R. China.
authors.forename: Dong
authors.initials: D
authors.lastname: Huang
authors.affiliation: Division of Cardiology, Tengzhou Central People's Hospital, Tengzhou, Shandong 277500, P.R. China.
authors.forename: Fa-Bin
authors.initials: FB
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Tengzhou Central People's Hospital, Tengzhou, Shandong 277500, P.R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Guo
authors.affiliation: Division of Cardiology, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai Jiaotong University School of Medicine, State Key Discipline Division, Shanghai 200233, P.R. China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.affiliation: Division of Cardiology, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai Jiaotong University School of Medicine, State Key Discipline Division, Shanghai 200233, P.R. China.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Yan
authors.affiliation: Division of Cardiology, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai Jiaotong University School of Medicine, State Key Discipline Division, Shanghai 200233, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.affiliation: Division of Cardiology, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai Jiaotong University School of Medicine, State Key Discipline Division, Shanghai 200233, P.R. China.
authors.forename: Meng
authors.initials: M
authors.lastname: Wei
authors.affiliation: Division of Cardiology, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai Jiaotong University School of Medicine, State Key Discipline Division, Shanghai 200233, P.R. China.
authors.forename: Jing-Bo
authors.initials: JB
authors.lastname: Li
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005355:Fibrosis; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D064546:Protein Kinase C beta / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D000068718:Rosuvastatin Calcium; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D064546:Protein Kinase C beta