ABC | Volume 111, Nº2, August 2018

Original Article Zhong et al Pioglitazone and VEGFR-2 signaling pathway Arq Bras Cardiol. 2018; 111(2):162-169 Figure 1 – VEGFR-2 is the potential target of pioglitazone. A, 3D molecular docking model of pioglitazone with VEGFR-2; green structure, the conformer of pioglitazone. B, 2D molecular docking model of pioglitazone with VEGFR-2; purple structure, the conformer of pioglitazone. H-bonding interactions between the pioglitazone and VEGFR-2 were indicated with green dashed lines. C and D, Representative western bolotting trace of VEGFR-2 and phospho-VEGFR-2 (Tyr1175) protein levels in rat neonatal cardiomyocytes under hypertrophic stimuli, and treated with 0, 10, 20 (μM) pioglitazone for 24 hours, and intensity of the bands in C normalized to β-actin (n = 12 in each group). All data shown are the mean ± SD. *p < 0.01 compared with control; #p < 0.01 compared with pioglitazone 10 μM group, calculated by one-way ANOVA followed by the post hoc Bonferroni test for pairwise comparisons. A B C D Pioglitazone Pioglitazone (µM) 0 10 20 pVEGFR2 (Tyr1175) VEGFR2 β-actin * *# Control Pioglitazone 10 µM Pioglitazone 20 µM 1.5 1.0 0.5 0.0 Normalized pVEGFR2 (Tyr1175) levels expression of phosphorylated VEGFR-2, Akt, andmTOR in vitro . These findings suggest that pioglitazone induces cardiomyocyte apoptosis and inhibits cardiomyocyte hypertrophy through effects on the VEGFR-2 signaling pathway. Pioglitazone has been widely used to improve glycemic control in patients with type 2 DM. Additionally, the PROactive trial showed that pioglitazone reduced the main secondary composite outcome of cardiovascular death/myocardial infarction/stroke vs. placebo by 43 % in the trial population. 10 These findings indicate that pioglitazone improves vascular function in diabetic patients and non-diabetic patients with insulin resistance and suggesting a possible beneficial effect of pioglitazone treatment on cardiovascular prognosis. Furthermore, a meta-analysis showed that supplementing insulin treatment with pioglitazone in type 2 DM patients with poorly controlled glucose levels could help decrease glucose levels and reduce the daily insulin dose without increasing the risks of myocardial infarction, HF, cardiac death and all-cause death, but at the cost of increasing total cholesterol levels and risks of hypoglycemia and edema. 20 Given available evidence, pioglitazone treatment appears advantageous in patients with HF. However, pioglitazone was also reported to increase the risk of hospitalization for HF over a 30-day period, even though patients at high risk of HF were unlikely to be prescribed the drug. 21 Furthermore, clinical studies indicated that low dose pioglitazone treatment does not reduce the rate of in-stent restenosis, neointima volume nor atheroma volume in DM patients who have undergone percutaneous coronary intervention with drug-eluting stents. 22 Beyond different methodologies applied in the discussed studies, reasons for contradictory reports on effects of pioglitazone on HF remain unclear. Investigating cardiovascular targets of pioglitazone is a promising approach for clarifying the effect of the drug on cardiovascular outcomes. Effects of pioglitazone on the cardiovascular system have been previously reported. Pioglitazone attenuated monocrotaline-induced rat right ventricular hypertrophy and fibrosis and decreased cardiomyocyte size. 23 Pioglitazone (2.5 mg/kg) ameliorated systolic and diastolic cardiac dysfunction in a rat model of Ang II-induced 165