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GW24-e3699 Rosuvastatin protects cardiomyocytes from tumour necrosis factor-alpha induced apoptosis via microRNA-210 up-regulation
  1. Gao Yan-hua1,
  2. Xu Jian-fen1,2,
  3. Fu Ming-qiang1,
  4. Lou Yi1,
  5. Sun Ai-jun1,2,
  6. Zou Yun-zeng1,2,
  7. Ge Jun-bo1,2,
  8. Qian Ju-ying1
  1. 1Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
  2. 2Institutes of Biomedical Sciences, Fudan University, Shanghai, China

Abstract

Objectives To investigate the effects of statin, possessed pleiotropic cardioprotective effects, on cardiomyocytes apoptosis induced by TNF-α and the potential mechanisms involved.

Methods Cardiomyocytes isolated from neonatal rats were pretreated with rosuvastatin and followed by incubation with or without TNF-α. Cellular apoptosis was analysed by TUNEL assay, Hochest staining and caspase-3 activity detection. Expression level of miR-210 was determined by real-time PCR and the activity of NF-κB pathway was determined by Western-bolt. Up-regulation or knockdown of miR-210 was addressed by lentivirus transfection. The role of NF-κB in TNF-α induced cell apoptosis was also identified through the incubation of specific agonist to NF-κB pathway.

Results Compared with the control group, exposure to TNF-α resulted in a notably increase in cell apoptosis (5.42 ± 1.67% vs. 38.4 ± 6.77%, P<0.05), expression of cleaved caspase-3 (1.00 ± 0.38 vs. 3.78 ± 0.85, P<0.05) and activation of NF-κB pathway (1.00 ± 0.45 vs. 4.37 ± 0.66, P<0.05), while these effects could be significantly reduced by pretreatment with rosuvastatin. Inhibition experiment using NF-κB specific agonist reversed the anti-apoptotic effect of rosuvastatin (15.3 ± 6.48% vs. 26.3 ± 5.79%, P<0.05), indicating the cardioprotective effect of rosuvastatin, at least partly, dependent on NF-κB signalling. Real-time PCR showed that TNF-α incubation decreased the expression of miR-210 (1.00 ± 0.26 vs. 0.57 ± 0.38, P<0.05) in cardiomyocytes and this decrease was reversed by the pretreatment of rosuvastatin in a dose-dependent way. Overexpression of miR-210 decreased cardiomyocytes apoptosis induced by TNF-α (19.6 ± 6.68% vs. 33.5 ± 3.84%, P<0.05), similarly to statin pretreatment. Most importantly, the anti-apoptotic effect of rosuvastatin was significantly reduced by the transfection of antigomiR-210 (15.8 ± 4.28% vs. 30.7 ± 5.22%, P<0.05), which was statistically abolished by a putative target RGMA knockdown (30.7 ± 5.22% vs. 20.3 ± 3.38%, P<0.05).

Conclusions Rosuvastatain protected cardiomyocytes from TNF-α induced apoptosis through the inhibition of NF-κB pathway and upregulation of miR-210.

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