Department of Biotechnology and SRM Research Institute, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India.
Indian Institute of Food Processing Technology, Pudukkottai Road, Thanjavur, 613005, Tamil Nadu, India.
Free Radic Biol Med. 2020 Aug 20;156:168-175. doi: 10.1016/j.freeradbiomed.2020.05.018. Epub 2020 May 27.
Diabetic non healing wounds often result in significant morbidity and mortality. The number of effective targets to detect these wounds are meagre. Slow lymphangiogenesis is one of the complex processes involved in impaired healing of wounds. Long non coding RNAs (lncRNAs) have been importantly recognized for their role in pathological conditions. Multiple studies highlighting the role of lncRNAs in the regulation of several biological processes and complex diseases. Herein, we investigated the role of lncRNA Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in the progression of diabetic foot ulcer (DFU). We report a significant reduction in the expression of lncRNA MALAT1 in the infected DFU subjects which was positively correlated with the expression of angiogenic factors such as Nrf2, HIF-1α and VEGF. Further, expression of pro-inflammatory markers TNF-α and IL-6 were found to be increased while, the expression of anti-inflammatory marker IL-10 was decreased in infected DFU tissues. Involvement of lncRNA MALAT1 in angiogenesis in EA.hy926 cells was demonstrated by silencing the expression of Nrf2, HIF-1α, and VEGF through interference mediated by MALAT1. In addition, its inflammatory role was demonstrated by decreased expression of TNF-α, IL-6 and not affecting the expression of IL-10. Further, CRISPR-Cas9 knock out of Nrf2 decreased the expression of lncRNA MALAT1, HIF-1α and VEGF which revealed the association of Nrf2 in regulating MALAT1/HIF-1α loop through positive feedback mechanism. Collectively, our results suggested the role of Nrf2 on MALAT1/HIF-1α loop in the regulation of angiogenesis, which could act as a novel target in the treatment of diabetic wounds.
糖尿病不愈合的伤口常导致显著的发病率和死亡率。可用于检测这些伤口的有效靶点数量很少。淋巴血管生成缓慢是伤口愈合受损的复杂过程之一。长链非编码 RNA（lncRNA）因其在病理状态下的作用而受到重要重视。多项研究强调了 lncRNA 在调节多种生物过程和复杂疾病中的作用。在此，我们研究了 lncRNA 转移相关肺腺癌转录本 1（MALAT1）在糖尿病足溃疡（DFU）进展中的作用。我们报告说，在感染的 DFU 受试者中，lncRNA MALAT1 的表达显著降低，这与血管生成因子如 Nrf2、HIF-1α 和 VEGF 的表达呈正相关。此外，在感染的 DFU 组织中发现促炎标志物 TNF-α 和 IL-6 的表达增加，而抗炎标志物 IL-10 的表达减少。通过 MALAT1 介导的干扰，沉默 Nrf2、HIF-1α 和 VEGF 的表达，证明了 lncRNA MALAT1 参与 EA.hy926 细胞的血管生成。此外，通过降低 TNF-α、IL-6 的表达而不影响 IL-10 的表达，证明了其炎症作用。进一步的，CRISPR-Cas9 敲除 Nrf2 降低了 lncRNA MALAT1、HIF-1α 和 VEGF 的表达，这表明 Nrf2 通过正反馈机制在调节 MALAT1/HIF-1α 环中起作用。总之，我们的结果表明 Nrf2 在 MALAT1/HIF-1α 环中对血管生成的调节作用，这可能成为治疗糖尿病伤口的新靶点。
