Nrf-2 signaling inhibits intracranial aneurysm formation and progression by modulating vascular smooth muscle cell phenotype and function

  • J Neuroinflammation. 2019 Oct 4;16(1):185. doi: 10.1186/s12974-019-1568-3.
Yuan Shi  1 ,  Sichen Li  1 ,  Yaying Song  2 ,  Peixi Liu  1 ,  Zixiao Yang  1 ,  Yingjun Liu  1 ,  Kai Quan  1 ,  Guo Yu  1 ,  Zhiyuan Fan  1 ,  Wei Zhu  3
Affiliations
  • 1. Department of Neurosurgery, Huashan Hospital, Fudan University, 12 Wulumiqi Rd., Shanghai, 200040, People's Republic of China.
  • 2. Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Rd. No.2, Shanghai, 200025, China.
  • 3. Department of Neurosurgery, Huashan Hospital, Fudan University, 12 Wulumiqi Rd., Shanghai, 200040, People's Republic of China. [email protected].
PMID: 31585542 DOI: 10.1186/s12974-019-1568-3
Abstract

Background: Oxidative stress and vascular smooth muscle cell (VSMC) phenotypic modulation influence intracranial aneurysm (IA) formation and progression. Oxidative stress plays an important role in phenotype switching, and nuclear factor erythroid 2-related factor 2 (Nrf-2) is one of the main antioxidant systems. Unfortunately, little is known about how Nrf-2 signaling influences VSMC phenotype switches during IA pathogenesis.

Methods: We examined the effect of Nrf-2 activation IA on formation and progression in an elastase-induced rat IA model. We also developed a hydrogen peroxide (H2O2)-induced VSMC oxidative damage model. Then, we analyzed VSMC phenotype changes in the setting of Nrf-2 activation or inhibition in vitro. The proliferation, migration ability, and Apoptosis rate of VSMCs were tested. Lastly, we measured the expression levels of antioxidant Enzymes and inflammatory cytokines downstream of Nrf-2.

Results: Nrf-2 activation suppressed IA formation and progression in vivo. We confirmed Nrf-2 nuclear translocation and a VSMC switch from the contractile to synthetic phenotype. Nrf-2 activation inhibited the proliferation, migratory ability, and Apoptosis rate enhanced by H2O2. Quantitative real-time polymerase chain reaction (PCR) and western blot analysis revealed that Nrf-2 activation promoted antioxidant Enzymes and VSMC-specific marker gene expressions but decreased pro-inflammatory cytokine levels.

Conclusion: These results suggest that Nrf-2 exerts protective effects against IA development by preventing VSMCs from changing to a synthetic phenotype.

Keywords
Inflammation; Intracranial aneurysm; Nrf-2; Oxidative stress; Vascular smooth muscle cells phenotype.
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