Article Text

GW24-e3737 MicroRNA-210 mediates the protective effect of nitrate on endothelial progenitor cells against senescence induced by angiotensin II through suppressing gene SCH9
  1. Xu Jianfeng1,2,
  2. Qian Juying1,
  3. Lin Li3,
  4. Gao Yanhua1,
  5. Shen Li1,
  6. Fu Mingqiang1,
  7. Zou Yunzeng1,
  8. Sun Aijun1,
  9. Zhang Dadong2,
  10. Ge Junbo1
  1. 1Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
  2. 2Department of Cardiology, Central Hospital of Minghang District, Shanghai 201199, China
  3. 3Department of Cardiology, East Hospital, Tongji University, Shanghai 200120, China


Objectives To examine a hypothesis that organic nitrate, widely used to treat vascular contraction, protects endothelial progenitor cells (EPCs) against senescence induced by angiotensinII (AngII); and if so, to investigate the underlying mechanisms involved.

Methods Human-derived EPCs, treated with PBS or nitrate (100 μmol/L), was subsequently exposed to AngII (100 nmol/L) for 24 hours in vitro. The senescence-associated β-galactosidase test and the detection of p16Ink4a/p19Arf expression were used to evaluate the cellular senescence. The miRNAs transcriptome was analysed by microarray and was verified by real-time PCR. The gain- and loss-of-function methods through lentivirus infection were administrated to evaluate the role of miRs in the senescence of EPCs induced by angiotensinII. Additionally, a luciferase reporter assay was performed to confirm associations between miRNAs and their putative targets, which was furthermore verified by small interference RNA (siRNA) and Western-blot.

Results AngII significantly induced EPCs senescence while nitrate not. However, the effect of AngII on cellular senescence could be statistically attenuated by nitrate pre-culture, indicated as the differences in the percentage of senescent EPCs between AngII group and pre-culture group [(72.6 ± 6.92)% vs. (43.7 ± 7.55)%, P<0.05], as well as the expressions of p16Ink4a (3.56 ± 0.76 vs. 1.93 ± 0.42, P<0.05) and p19Arf (4.88 ± 0.72 vs. 2.67 ± 0.54, P<0.05). MiR-210 in pre-culture group was discovered to up-regulate more over 4 times than that in AngII group (P<0.05). Moreover, forced expression of miR-210 in EPCs, compared with scramble over-expression, was evidenced to dramatically reverse cell senescence induced by AngII [(37.6 ± 7.43)% vs. (71.8 ± 6.63)%, P<0.05] and drastically decrease both p16Ink4a and p19Arf expressions (both P<0.05). In contrast, suppression of miR-210 in EPCs, raising putative miR-target SCH9 expression, statistically abolished the protective effect of nitrate on EPCs senescence [anti-miR group vs. null group: (72.6 ± 6.92)% vs. (45.8 ± 8.39)%, P<0.05]. Most importantly, the phenotypic changes were discovered to be recovered by SCH9 knockdown (P<0.05).

Conclusions Nitrate protects EPCs, mediated by miR-210 up-regulation and SCH9 suppression, against cellular senescence induced by AngII, which is of a crucial significance for those rennin-dependent hypertensive patients with vascular injury.

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