Role of Nrf2 in MALAT1/ HIF-1α loop on the regulation of angiogenesis in diabetic foot ulcer

Abstract

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.

Keywords: Angiogenesis; Diabetic foot ulcer; Inflammation; MALAT1; Nrf2; RNA interference; lncRNA.