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Protective role of NRF2 in macrovascular complications of diabetes
Junduo Wu1, Xiaodan Sun2, Ziping Jiang3
1Department of Cardiology, The Second Hospital of Jilin University, Changchun, China.
Abstract:
Macrovascular complications develop in over a half of the diabetic individuals, resulting in high morbidity and mortality. This poses a severe threat to public health and a heavy burden to social economy. It is therefore important to develop effective approaches to prevent or slow down the pathogenesis and progression of macrovascular complications of diabetes (MCD). Oxidative stress is a major contributor to MCD. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) governs cellular antioxidant defence system by activating the transcription of various antioxidant genes, combating diabetes-induced oxidative stress. Accumulating experimental evidence has demonstrated that NRF2 activation protects against MCD. Structural inhibition of Kelch-like ECH-associated protein 1 (KEAP1) is a canonical way to activate NRF2. More recently, novel approaches, such as activation of the Nfe2l2 gene transcription, decreasing KEAP1 protein level by microRNA-induced degradation of Keap1 mRNA, prevention of proteasomal degradation of NRF2 protein and modulation of other upstream regulators of NRF2, have emerged in prevention of MCD. This review provides a brief introduction of the pathophysiology of MCD and the role of oxidative stress in the pathogenesis of MCD. By reviewing previous work on the activation of NRF2 in MCD, we summarize strategies to activate NRF2, providing clues for future intervention of MCD. Controversies over NRF2 activation and future perspectives are also provided in this review.
Insights
Nuclear factor (erythroid-derived 2)-like 2 (NRF2) activation combats oxidative stress, protecting against diabetic macrovascular complications (MCD). This review summarizes NRF2 activation strategies for preventing and treating MCD.
Area of Science:
- Biomedical Science
- Molecular Biology
- Pathophysiology
Background:
- Macrovascular complications (MCD) affect over half of diabetic individuals, causing significant morbidity and mortality.
- Oxidative stress is a key contributor to the pathogenesis and progression of MCD.
- Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of cellular antioxidant defense against diabetes-induced oxidative stress.
Purpose of the Study:
- To review the pathophysiology of MCD and the role of oxidative stress.
- To summarize current strategies for activating NRF2 to prevent or slow MCD progression.
- To provide insights into future therapeutic interventions for MCD.
Main Methods:
- Literature review of experimental evidence on NRF2 activation in MCD.
- Analysis of canonical and novel approaches to NRF2 activation.
- Discussion of upstream regulators of NRF2 and their role in MCD.
Main Results:
- NRF2 activation has been experimentally shown to protect against MCD.
- Canonical NRF2 activation involves structural inhibition of Kelch-like ECH-associated protein 1 (KEAP1).
- Novel strategies include Nfe2l2 gene transcription activation, microRNA-mediated Keap1 mRNA degradation, and NRF2 protein stabilization.
Conclusions:
- NRF2 activation represents a promising therapeutic strategy for preventing and managing diabetic macrovascular complications.
- Further research into novel NRF2 activation pathways and their clinical translation is warranted.
- Addressing controversies and exploring future perspectives in NRF2 modulation is crucial for effective MCD intervention.
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