Activation of Nrf2 signaling: A key molecular mechanism of protection against cardiovascular diseases by natural products

Abstract

Cardiovascular diseases (CVD) are a group of cardiac and vascular disorders including myocardial ischemia, congenital heart disease, heart failure, hypertension, atherosclerosis, peripheral artery disease, rheumatic heart disease, and cardiomyopathies. Despite considerable progress in prophylaxis and treatment options, CVDs remain a leading cause of morbidity and mortality and impose an extremely high socioeconomic burden. Oxidative stress (OS) caused by disequilibrium in the generation of reactive oxygen species plays a crucial role in the pathophysiology of CVDs. Nuclear erythroid 2-related factor 2 (Nrf2), a transcription factor of endogenous antioxidant defense systems against OS, is considered an ideal therapeutic target for management of CVDs. Increasingly, natural products have emerged as a potential source of Nrf2 activators with cardioprotective properties and may therefore provide a novel therapeutic tool for CVD. Here, we present an updated comprehensive summary of naturally occurring products with cardioprotective properties that exert their effects by suppression of OS through activation of Nrf2 signaling, with the aim of providing useful insights for the development of therapeutic strategies exploiting natural products.

Targeting the redox system for cardiovascular regeneration in aging

“…Several pharmacological redox regulators, both natural and synthetic, have been identified to directly or indirectly protect cardiovascular stem/progenitor cells and optimize cell‐based cardiovascular regenerative therapies. Many of these redox‐modulating small molecules function by inducing Nrf2 and downstream antioxidant enzymes, particularly HO‐1, to regulate the oxidant–antioxidant interplay in cardiovascular stem/progenitor cells and pluripotent stem cells crucial for generating cardiovascular lineages (Loboda et al., 2016 ; Wu et al., 2022 ). Additionally, these compounds inhibit oxidative pathways by downregulating the NOX family (Zhang, Murugesan, et al., 2020 ; Zhang, Zhang, et al., 2020 ) or enhance antioxidant defense (Shafi et al., 2019 ; Suzuki & Shults, 2019 ) by upregulating sirtuins (Xie et al., 2023 ) or releasing hydrogen sulfide (Zhang et al., 2018 ) in the cells.…”

AEOL-Induced NRF2 Activation and DWORF Overexpression Mitigate Myocardial I/R Injury

“…Reductions in cardiac nuclear translocation of NRF2 and the expression of HO-1 and p62 were accompanied by upregulated autophagy, increased apoptosis, and cardiac dysfunction after mI/R injury, effects that were prevented by AEOL treatment early after reperfusion onset. ROS accumulation increases signi cantly during the acute phase of cardiac reperfusion, triggering a reparative response associated with NRF2 activation 37 .…”

“…Unfortunately, this activation is transient, as evidenced by our nding of a substantial decline in Nrf2 mRNA levels and activity just 24 h post-reperfusion. Enhancing NRF2 activity, including approaches promoting NRF2 nuclear translocation, is thus an attractive cardioprotective strategy with potential application in AMI [37][38][39] . While previous studies examined AEOL's potential to mitigate radiation-induced lung injury in large animal models 21,23,40,41 , alleviate anthracycline-induced cardiotoxicity 22 , and even reduce ischemic brain damage 42 , ours is the rst study to explore the potential applicability and therapeutic e cacy of AEOL in mitigating cardiac mI/R injury and preventing CHF.…”

Berberine modulates cardiovascular diseases as a multitarget-mediated alkaloid with insights into its downstream signals using in silico prospective screening approaches

“…Atherosclerotic CVDs are resulted from permeation and accumulation of ox-LDLs into the arterial intima. Modified LDLs (ox-LDLs) accelerates formation of endothelial lesions, atherosclerotic plaques burden, and macrophage foam cells ( Wu et al, 2022 ). Transcription factor Nrf2 and its downstream targets as reduced GSH, GPx, GST, GR, SOD, CAT, NQO1, and HO-1 serve as potent master regulators to upregulate the cellular antioxidant defenses.…”

“…Transcription factor Nrf2 and its downstream targets as reduced GSH, GPx, GST, GR, SOD, CAT, NQO1, and HO-1 serve as potent master regulators to upregulate the cellular antioxidant defenses. These antioxidant modulators improve vascular endothelial cells dysfunction, foam cells and atherosclerotic lesions formation, pathogenesis of CVDs, and apoptosis through upregulating the cellular cholesterol uptake receptors and its efflux transporters signaling and alleviating the levels of vascular oxidative stress and pro-inflammatory modulators such as LPO, IL6, IL1β, TNFα, IFNγ, iNOS, and MCP-1 ( Ooi et al, 2018 , Wu et al, 2022 ). As proatherogenic factors, TNFα, IL6, MCP-1/CCL2, and MMP9 potentially accelerate monocytes migration and adhesion, induce endothelial cells dysfunction, accelerate foam cells formation, disturb macrophages cholesterol efflux signaling, and develop pathogenesis features of CVDs ( Huwait et al, 2021 , Wang et al, 2023 ).…”