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  • Title: Vasculoprotective effects of rosiglitazone through modulating renin-angiotensin system in vivo and vitro.
    Author: Ren L, Liu N, Zhi H, Li Y, Li Y, Tang R, Sheng Z.
    Journal: Cardiovasc Diabetol; 2011 Jan 26; 10():10. PubMed ID: 21269478.
    Abstract:
    BACKGROUND: The peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone has been suggested to exert cardiovascular protection through the improvement of lipid metabolism, anti-inflammation, anti-proliferation etc. However, whether renin-angiotensin system (RAS) is involved in the vascular protective effects of PPARγ agonists is not fully understood. The present study aimed to investigate the effects of the renin-angiotensin system in vascular protection mediated by PPARγ agonists. OBJECTIVE: To investigate the actions of the renin-angiotensin system in vascular protection mediated by activation of PPARγ in vivo and in vitro. METHODS: Rats were fed a regular diet (n = 8), a cholesterol-rich diet plus methylthiouracil (80 mg/Kg/day, n = 10), a cholesterol-rich diet plus methylthiouracil and rosiglitazone (4 mg/kg/day, n = 10). The rosiglitazone treatment was started from one month after the start of cholesterol-rich diet plus methylthiouracil, and lasted five months. Cultured vascular smooth muscle cells (VSMCs) were pretreated with 1 μmol/L angiotensin II (ANG II) for 6 h and randomly divided into the control group; the ANG II group (1 μmol/L ANG II); the groups respectively treated with different concentration rosiglitazone (20, 30, 50) μmol/L for 12 h; the groups treated with 30 μmol/L rosiglitazone for (6, 12, 24) h. Morphology changes of the aortic tissues were observed by hematoxylin and eosin stain. The VSMC growth was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. Angiotensin II and expression of angiotensin receptors were determined by radioimmunoassay, reverse transcription polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry. RESULTS: After 6 months, lipid deposition, VSMC proliferation and migration toward intima were observed in aortic tissues in the rats on a cholesterol-rich diet plus methylthiouracil, while these pathological changes induced by the cholesterol-rich diet were significantly suppressed by rosiglitazone. In addition, VSMC proliferation induced by ANG II was markedly inhibited by rosiglitazone. Rosiglitazone markedly down-regulated expression of angiotensin type 1 receptor (AT1R) and up-regulated expression of angiotensin type 2 receptor (AT2R) in the aortic tissues and ANG II-treated VSMCs. CONCLUSIONS: The present study demonstrated that PPARγ agonist rosiglitazone suppressed ANG II-induced VSMC proliferation in vitro and early atherosclerotic formation evoked by cholesterol-rich diet in vivo. These vasculoprotective effects of rosiglitazone were mediated at least partially by reduction in local tissue ANG II concentration, down-regulation of AT1R expression and up-regulation of AT2R expression both at the mRNA and protein levels.
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