Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, TN, 603210, India.
Department of Molecular Genetics, M.V. Hospital for Diabetes & Prof. M. Viswanathan Diabetes Research Centre, Royapuram, Chennai, India.
Arch Biochem Biophys. 2024 Oct;760:110133. doi: 10.1016/j.abb.2024.110133. Epub 2024 Aug 22.
Nuclear factor E2-related factor 2 (Nrf2), a redox-sensitive transcription factor, regulates proangiogenic mediators, and antioxidant and detoxification enzymes. However, hitherto its regulation in the progression of DFU was poorly examined. The regulation of Nrf2 has been reported to be affected by various factors, including histone deacetylase (HDACs) and DNA methylation. The present study aimed to profile all classes of HDACs and correlate them with Nrf2 and angiogenic markers in the tissue biopsies of different grades of DFU patients (n = 20 in each grade). The gene expression profile of Nrf2 and its downstream targets, angiogenic markers, and all classes of HDACs were assessed using qPCR. Spearman's correlation was performed to analyze the correlation of HDACs with Nrf2 and its downstream targets along with angiogenic markers. We observed a progressive decrease in the gene expression of Nrf2 and angiogenic markers such as VEGF, HIF-1α, and SDF-1α and also an increase in the TSP-2 expression in different grades of DFU. In parallel, a significant downregulation of HDAC2/8 and SIRT1/2/4 has been observed in various grades of DFU subjects. On the other hand, HDAC1/3/4/11 and SIRT3/5/6/7 showed upregulation in different grades of DFU and the maximum increase was observed in Grade 3 patients. A significant negative correlation between Nrf2 and HDAC4, angiogenic markers, and HDAC4 suggested the pivotal role of the HDAC4-regulated Nrf2-mediated angiogenesis among DFU subjects. We have generated a first line of evidence on the epigenetic regulation of Nrf2 and its correlation with angiogenesis in the progression of diabetic foot ulcers.
核因子 E2 相关因子 2（Nrf2）是一种氧化还原敏感的转录因子，可调节促血管生成介质、抗氧化和解毒酶。然而，迄今为止，其在糖尿病足溃疡（DFU）进展中的调节作用仍未得到充分研究。已有报道称，Nrf2 的调节受多种因素的影响，包括组蛋白去乙酰化酶（HDACs）和 DNA 甲基化。本研究旨在分析所有 HDAC 类别的表达谱，并与不同等级 DFU 患者组织活检中的 Nrf2 和血管生成标志物相关联（每个等级 20 例）。采用 qPCR 评估 Nrf2 及其下游靶标、血管生成标志物和所有 HDAC 类别的基因表达谱。采用 Spearman 相关分析评估 HDACs 与 Nrf2 及其下游靶标和血管生成标志物的相关性。我们观察到，随着 DFU 分级的增加，Nrf2 和血管生成标志物（如 VEGF、HIF-1α 和 SDF-1α）的基因表达逐渐降低，TSP-2 的表达逐渐增加。与此同时，我们还观察到，在不同分级的 DFU 患者中，HDAC2/8 和 SIRT1/2/4 的表达显著下调。另一方面，HDAC1/3/4/11 和 SIRT3/5/6/7 的表达在不同分级的 DFU 中上调，在 3 级患者中表达增加最大。Nrf2 与 HDAC4、血管生成标志物和 HDAC4 之间存在显著的负相关，这表明在 DFU 患者中，HDAC4 调节的 Nrf2 介导的血管生成起关键作用。本研究首次提供了 Nrf2 的表观遗传调控及其与糖尿病足溃疡进展中血管生成相关性的证据。
