Knockdown of long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 protects against intracerebral hemorrhage through microRNA-146a-mediated inhibition of inflammation and oxidative stress

Zhanyi Xu  ¹ , Baoshuai Zhao  ¹ , Jianhui Mao  ¹ , Zhaosheng Sun  ¹ Affiliations

• PMID: 35113000
• PMCID: PMC8974162
• DOI: 10.1080/21655979.2022.2031401

Free PMC article

Abstract

Studies have demonstrated that long noncoding RNAs (lncRNAs) are important regulators of intracerebral hemorrhage (ICH) and participants in ICH pathogenesis. We designed this study to probe the potential functions and mechanisms of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in ICH. The ICH model was established and the rats were treated with MALAT1-shRNA or MALAT1-shRNA+miR-146a inhibitor 1 h after ICH induction. A dual-luciferase reporter assay was employed to examine the relationship between MALAT1 and miR-146a. In addition, rat neurobehavioral changes, brain water content, and neuronal apoptosis were measured in this study. Furthermore, the pro‑inflammatory markers tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1β were determined by enzyme-linked immunosorbent assays (ELISAs), while the oxidative stress factors, including malondialdehyde (MDA) and superoxide dismutase (SOD), were also evaluated. Lastly, a Western blot assay was employed to examine the protein levels of phosphorylated (p)-p65 and p65. First, we found that MALAT1 was expressed at higher levels in ICH rats. miR-146a is a target gene of MALAT1 and is downregulated in ICH rats. Downregulation of MALAT1 inhibited the neurological scores, brain water content, and neuronal apoptosis, reduced the levels of pro-inflammatory cytokines, and prevented oxidative stress in ICH rats. In addition, the protein level of p-p65 and the ratio of p-p65/p65 were decreased in the MALAT1-shRNA group. All the effects of MALAT1-shRNA on ICH rats were reversed by miR-146a inhibitor co-treatment. In conclusion, downregulation of MALAT1 protected against ICH by suppressing inflammation and oxidative stress by upregulating miR-146a.

Keywords: Intracerebral hemorrhage; inflammation; lncRNA MALAT1; miR-146a; oxidative stress.