Nrf2 and Heme Oxygenase-1 Involvement in Atherosclerosis Related Oxidative Stress

Alonso-Piñeiro, José Ángel; González-Rovira, Almudena; Sánchez-Gomar, Ismael; Moreno, Juan Antonio; Durán-Ruiz, Ma Carmen

doi:10.3390/antiox10091463

Cited by 63 publications

(48 citation statements)

References 175 publications

(303 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A large number of studies have described the involvement of the Nrf2 antioxidant system in the prevention or attenuation of age-related diseases including atherosclerosis, vascular calcification, cataract formation, and macular degeneration [ 21 , 25 , 33 , 46 , 47 , 48 ]. There are numerous clinical trials targeting the Nrf2 system in diverse clinical conditions including cancer, chronic kidney disease, diabetes, aging problems, etc.…”

Section: Discussionmentioning

confidence: 99%

Activation of Nrf2/HO-1 Antioxidant Pathway by Heme Attenuates Calcification of Human Lens Epithelial Cells

et al. 2022

View full text Add to dashboard Cite

Cataract, an opacification in the crystalline lens, is a leading cause of blindness. Deposition of hydroxyapatite occurs in a cataractous lens that could be the consequence of osteogenic differentiation of lens epithelial cells (LECs). Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the transcription of a wide range of cytoprotective genes. Nrf2 upregulation attenuates cataract formation. Here we aimed to investigate the effect of Nrf2 system upregulation in LECs calcification. We induced osteogenic differentiation of human LECs (HuLECs) with increased phosphate and calcium-containing osteogenic medium (OM). OM-induced calcium and osteocalcin deposition in HuLECs. We used heme to activate Nrf2, which strongly upregulated the expression of Nrf2 and heme oxygenase-1 (HO-1). Heme-mediated Nrf2 activation was dependent on the production of reactive oxygens species. Heme inhibited Ca deposition, and the OM-induced increase of osteogenic markers, RUNX2, alkaline phosphatase, and OCN. Anti-calcification effect of heme was lost when the transcriptional activity of Nrf2 or the enzyme activity of HO-1 was blocked with pharmacological inhibitors. Among products of HO-1 catalyzed heme degradation iron mimicked the anti-calcification effect of heme. We concluded that heme-induced upregulation of the Nrf2/HO-1 system inhibits HuLECs calcification through the liberation of heme iron.

show abstract

Section: Discussionmentioning

confidence: 99%

Activation of Nrf2/HO-1 Antioxidant Pathway by Heme Attenuates Calcification of Human Lens Epithelial Cells

et al. 2022

View full text Add to dashboard Cite

show abstract

“…In fact, hyperglycemia-induced ROS accumulation and hyperglycemia cause endothelial cell apoptosis and inflammation, resulting in endothelial injury (reviewed in [ 6 ]). The pathogenesis of atherosclerosis includes oxidative stress, high levels of oxidized lipoproteins, immune reactivity, and inflammation, as well (reviewed in [ 3 , 7 , 8 ]). Importantly, vascular endothelial dysfunction caused by dyslipidemia is considered the main factor for the beginning of atherosclerosis (reviewed in [ 8 , 9 ]).…”

Section: Introductionmentioning

confidence: 99%

“…The pathogenesis of atherosclerosis includes oxidative stress, high levels of oxidized lipoproteins, immune reactivity, and inflammation, as well (reviewed in [ 3 , 7 , 8 ]). Importantly, vascular endothelial dysfunction caused by dyslipidemia is considered the main factor for the beginning of atherosclerosis (reviewed in [ 8 , 9 ]).…”

Section: Introductionmentioning

confidence: 99%

The Role of NRF2 in Obesity-Associated Cardiovascular Risk Factors

et al. 2022

View full text Add to dashboard Cite

The raising prevalence of obesity is associated with an increased risk for cardiovascular diseases (CVDs), particularly coronary artery disease (CAD), and heart failure, including atrial fibrillation, ventricular arrhythmias and sudden death. Obesity contributes directly to incident cardiovascular risk factors, including hyperglycemia or diabetes, dyslipidemia, and hypertension, which are involved in atherosclerosis, including structural and functional cardiac alterations, which lead to cardiac dysfunction. CVDs are the main cause of morbidity and mortality worldwide. In obesity, visceral and epicardial adipose tissue generate inflammatory cytokines and reactive oxygen species (ROS), which induce oxidative stress and contribute to the pathogenesis of CVDs. Nuclear factor erythroid 2-related factor 2 (NRF2; encoded by Nfe2l2 gene) protects against oxidative stress and electrophilic stress. NRF2 participates in the regulation of cell inflammatory responses and lipid metabolism, including the expression of over 1000 genes in the cell under normal and stressed environments. NRF2 is downregulated in diabetes, hypertension, and inflammation. Nfe2l2 knockout mice develop structural and functional cardiac alterations, and NRF2 deficiency in macrophages increases atherosclerosis. Given the endothelial and cardiac protective effects of NRF2 in experimental models, its activation using pharmacological or natural products is a promising therapeutic approach for obesity and CVDs. This review provides a comprehensive summary of the current knowledge on the role of NRF2 in obesity-associated cardiovascular risk factors.

show abstract

“…In addition, pharmacological activation of Nrf2 suppresses endothelial pyroptosis by reducing the overproduction of ROS ( 16 ). It is reported that Nrf2 may be an ideal therapeutic target for prevention of diabetic atherosclerosis ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

Exogenous spermine inhibits high glucose/oxidized LDL‑induced oxidative stress and macrophage pyroptosis by activating the Nrf2 pathway

Qiu

Li²,

X³

et al. 2022

Exp Ther Med

View full text Add to dashboard Cite

Evidence suggests that macrophage pyroptosis promotes the progression of diabetic atherosclerosis. Spermine, a natural cellular metabolite, demonstrates a protective effect against cardiovascular diseases. However, whether spermine has a protective effect against macrophage pyroptosis caused by high glucose (HG) and oxidized low-density lipoprotein (ox-LDL) conditions remains to be elucidated. To investigate the protective effect of spermine and the related underlying mechanism, THP-1 macrophages were treated with HG/ox-LDL, spermine, or the specific nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML385. Cell viability was detected using CCK-8, cell membrane permeability was analyzed using lactate dehydrogenase (LDH) and Hoechst/propidium iodide staining and pyroptosis-related gene and protein expression levels were evaluated using polymerase chain reaction and western blot analysis. Spermine showed a potent preventive effect on THP-1 macrophage pyroptosis and oxidative stress induced by HG/ox-LDL. Cells treated with spermine showed increased cell viability, reduced reactive oxygen species (ROS) production, decreased LDH levels in the supernatant and reduced cell swelling. In addition, spermine significantly reduced NLR family pyrin domain containing 3, cleaved caspase-1, N-gasdermin D and IL-1β expression, as well as IL-1β levels in the supernatant. This demonstrated that the inhibition of pyroptosis and oxidative stress due to spermine was Nrf2 dependent. Furthermore, spermine enhanced Nrf2 nuclear translocation, thereby increasing heme oxygenase-1 and NADPH quinone oxidoreductase-1 expression, which subsequently reduced ROS production. In addition, the anti-pyroptotic and antioxidant effects of spermine were reversed by ML385 inhibition of Nrf2. It was concluded that spermine prevented macrophage pyroptosis and increased ROS overproduction by activating the Nrf2 pathway. The data suggested that spermine may be a potential novel drug for the treatment of diabetic atherosclerosis because it targets macrophage pyroptosis.

show abstract

Nrf2 and Heme Oxygenase-1 Involvement in Atherosclerosis Related Oxidative Stress

Cited by 63 publications

References 175 publications

Activation of Nrf2/HO-1 Antioxidant Pathway by Heme Attenuates Calcification of Human Lens Epithelial Cells

Activation of Nrf2/HO-1 Antioxidant Pathway by Heme Attenuates Calcification of Human Lens Epithelial Cells

The Role of NRF2 in Obesity-Associated Cardiovascular Risk Factors

Exogenous spermine inhibits high glucose/oxidized LDL‑induced oxidative stress and macrophage pyroptosis by activating the Nrf2 pathway

Contact Info

Product

Resources

About