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Original research
NADPH oxidase inhibitor regulates microRNAs with improved outcome after mechanical reperfusion
  1. Zhong Liu1,
  2. Yong-Hua Tuo1,
  3. Jian-Wen Chen2,
  4. Qing-Yuan Wang1,
  5. Songlin Li3,
  6. Ming-Chang Li4,
  7. Gang Dai5,
  8. Jin-Shan Wang1,
  9. Yong-Li Zhang6,
  10. Lei Feng7,
  11. Zhong-Song Shi1,8
  1. 1Department of Neurosurgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
  2. 2School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
  3. 3The Institute of Life Sciences, Wenzhou University, Wenzhou, China
  4. 4Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
  5. 5Key Laboratory on Assisted Circulation of Ministry of Health, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
  6. 6Department of Biology, Guangdong Pharmaceutical University, Guangzhou, China
  7. 7Division of Interventional Neuroradiology, Kaiser Permanente Medical Center, Los Angeles, California, USA
  8. 8Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-sen University, Guangzhou, China
  1. Correspondence to Dr Zhong-Song Shi, Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Second Ave, Guangzhou, Guangdong 510080, China; shizhs{at}mail.sysu.edu.cn

Abstract

Background Inhibition of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) pathway improves the neurological outcome in the transient middle cerebral artery occlusion (tMCAO) animal model. In this study we analyzed the microRNAs profile targeting NOX2 and NOX4 genes and its response to NOX2/4 inhibitor VAS2870 to understand the mechanisms of this protective effect.

Methods The intraluminal filament tMCAO model was established in hyperglycemic rats (n=106) with 5 hours ischemia followed by 19 hours reperfusion. NOX inhibitor VAS2870 was delivered intravenously before reperfusion. Infarct volume, hemorrhagic transformation, and mortality were determined at 24 hours after cerebral ischemia. MicroRNAs profile targeting NOX2 and NOX4 genes were predicted by microRNA databases and further evaluated by microRNA microarray and quantitative RT-PCR.

Results Ten microRNAs potentially targeting NOX2 and NOX4 genes (including microRNA-29a, microRNA-29c, microRNA-126a, microRNA-132, microRNA-136, microRNA-138, microRNA-139, microRNA-153, microRNA-337, and microRNA-376a) were significantly downregulated in the ischemic hemisphere in the tMCAO group compared with the sham-operated group, as shown by microRNA microarray and quantitative RT-PCR (all p<0.05). Intravenous treatment with NOX inhibitor VAS2870 before reperfusion increased the expression of microRNA-29a, microRNA-29c, microRNA-126a, and microRNA-132 compared with the tMCAO group (all p<0.05).

Conclusions Several microRNAs potentially targeting NOX2 and NOX4 genes displayed altered levels in hyperglycemic rats with the tMCAO model, suggesting their regulatory roles and targeting potentials for acute ischemic stroke treatment. Targeting specific microRNAs may represent a novel intervention opportunity to improve outcome and reduce hemorrhagic transformation after mechanical reperfusion for acute ischemic stroke.

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