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

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 have proposed that highlight lncRNAs to be crucial molecules in regulating several biological processes and complex diseases. Herein, we investigate the role of lncRNA Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in the progression of diabetic foot ulcer. We report significant reduction in the expression of lncRNA MALAT1 in the infected Diabetic foot ulcers subjects which is positively correlated with the expression of angiogenic factors Nrf2, HIF-1α and VEGF. Further, expression of pro-inflammatory markers TNF-α and IL-6 increased while, the expression of anti-inflammatory marker IL-10 decreased in infected DFU tissues. Involvement of lncRNA MALAT1 in angiogenesis in EA.hy926 cells is demonstrated by silencing the expression of Nrf2, HIF-1α, and VEGF through interference mediated by MALAT1. Similarly, its inflammatory role is demonstrated by silencing the 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.