Gene Expression Profiling of Multiple Histone Deacetylases (HDAC) and Its Correlation with NRF2-Mediated Redox Regulation in the Pathogenesis of Diabetic Foot Ulcers.

Rajan Teena,Kesavan Rajesh,Umapathy Dhamodharan,Kunka Mohanram Ramkumar,Daoud Ali

doi:10.3390/biom10101466

Abstract

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a protein of the leucine zipper family, which mitigates inflammation and employs cytoprotective effects. Attempting to unravel the epigenetic regulation of type 2 diabetes mellitus (T2DM) and diabetic foot ulcer (DFU), we profiled the expression of eleven isoform-specific histone deacetylases (HDACs) and correlated them with NRF2 and cytokines. This study recruited a total of 60 subjects and categorized into DFU patients (n = 20), T2DM patients (n = 20), and healthy controls (n = 20). The DFU patients were subcategorized into uninfected and infected DFU (n = 10 each). We observed a progressive decline in the expression of NRF2 and its downstream targets among T2DM and DFU subjects. The inflammatory markers IL-6 and TNF-α were significantly upregulated, whereas anti-inflammatory marker IL-10 was significantly downregulated in DFU. Of note, a significant upregulation of HDAC1, 3, 4, 11, SIRT3 and downregulation of HDAC2,8, SIRT1, SIRT2, SIRT3, SIRT7 among DFU patients were observed. The significant positive correlation between NRF2 and SIRT1 in DFU patients suggested the vital role of NRF2/SIRT1 in redox homeostasis and angiogenesis. In contrast, the significant negative correlation between NRF2 and HDAC1, 3 and 4, implied an imbalance in NRF2-HDAC1, 3, 4 circuit. Furthermore, a significant positive correlation was observed between HDAC4 and IL-6, and the negative correlation between SIRT1 and IL-6 suggested the pro-inflammatory role of HDAC4 and the anti-inflammatory role of SIRT1 in NRF2 signaling. In conclusion, the epigenetic changes such as upregulation of HDAC1, 3, 4, 11, SIRT3 and downregulation of HDAC2, 8, SIRT1, SIRT2, SIRT6, SIRT7 and their association with NRF2 as well as inflammatory markers are suggestive of their roles in pathophysiology of T2DM and DFU.

Highlights

Diabetic foot ulcer (DFU) is an extremely prevalent complication of diabetes mellitus that causes ulcers in the lower limbs of the affected individuals
systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), HbA1c, total serum cholesterol (TSC), low-density lipoprotein cholesterol (LDL-c), Homeostatic model assessment of insulin resistance (HOMA-IR), urea, creatinine, C-reactive protein (CRP), ESR, and white blood cells (WBC) counts were observed to be significantly elevated in type 2 diabetes mellitus (T2DM) subjects when compared with NGT subjects
Infected DFU subjects had a significant increase in SBP, DBP, FPG, PPG, HbA1c, LDL-c, HOMA-IR, urea, CRP, ESR, and WBC counts when compared with uninfected DFU subjects

Summary

Introduction

Diabetic foot ulcer (DFU) is an extremely prevalent complication of diabetes mellitus that causes ulcers in the lower limbs of the affected individuals. The most critical factors include poor glycemic control, inflammation, oxidative stress, peripheral neuropathy, autonomic neuropathy, and micro and macroangiopathy [1]. It is widely accepted that treatment strategies that combat cellular oxidative stress bolster and accelerate the wound healing process [3]. One of the crucial transcription factors that combat cellular oxidative stress is nuclear factor erythroid-2-related factor 2 (NRF2), and it is encoded by the gene NRF2. A recent study from our laboratory has provided insight into the role of HBOT in restoring NRF2 levels and angiogenesis in DFU subjects [6]. The cellular mechanisms that downregulate NRF2 in T2DM and DFU are still unclear

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