Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023;55(2):2284890.
doi: 10.1080/07853890.2023.2284890. Epub 2023 Dec 1.

Activation of the Nrf-2/HO-1 signalling axis can alleviate metabolic syndrome in cardiovascular disease

Chi Liu  1   2 , Xingli Xu  3 , Xing He  4 , Junyi Ren  5 , Mingxuan Chi  1   2 , Gang Deng  6 , Guisen Li  1   2 , Moussa Ide Nasser  6
Affiliations
Review

Activation of the Nrf-2/HO-1 signalling axis can alleviate metabolic syndrome in cardiovascular disease

Chi Liu et al. Ann Med. 2023.

Abstract

Background: Cardiovascular disease (CVD) is widely observed in modern society. CVDs are responsible for the majority of fatalities, with heart attacks and strokes accounting for approximately 80% of these cases. Furthermore, a significant proportion of these deaths, precisely one-third, occurs in individuals under 70. Metabolic syndrome encompasses a range of diseases characterized by various physiological dysfunctions. These include increased inflammation in adipose tissue, enhanced cholesterol synthesis in the liver, impaired insulin secretion, insulin resistance, compromised vascular tone and integrity, endothelial dysfunction, and atheroma formation. These factors contribute to the development of metabolic disorders and significantly increase the likelihood of experiencing cardiovascular complications.Method: We selected studies that proposed hypotheses regarding metabolic disease syndrome and cardiovascular disease (CVD) and the role of Nrf2/HO-1 and factor regulation in CVD research investigations based on our searches of Medline and PubMed.Results: A total of 118 articles were included in the review, 16 of which exclusively addressed hypotheses about the role of Nrf2 on Glucose regulation, while 16 involved Cholesterol regulation. Likewise, 14 references were used to prove the importance of mitochondria on Nrf2. Multiple studies have provided evidence suggesting the involvement of Nrf2/HO-1 in various physiological processes, including metabolism and immune response. A total of 48 research articles and reviews have been used to highlight the role of metabolic syndrome and CVD.Conclusion: This review provides an overview of the literature on Nrf2/HO-1 and its role in metabolic disease syndrome and CVD.

Keywords: Metabolic syndrome; Nrf2/HO-1; cardiovascular diseases; mitochondrial; reactive oxygen stress.

PubMed Disclaimer

Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Relationship of glycolysis, β-cell proliferation, insulin signalling, and ROS production with CVD: after myocardial injury, many local processes are activated. ROS and cytokines are released, and neutrophils and monocytes accumulate in the blood vessels, leading to acute myocardial injury. At the cardiomyocyte level, important mechanisms include increased glycolysis, energy changes, increased oxidative stress, and β-cell proliferation. Additionally, to alleviate oxidative stress-induced abnormalities, HO-1 and Mn-SOD, which are Nrf2-targeted enzymes, increase insulin sensitivity by inhibiting PKC and JNK activation caused by a mitochondrial malfunction.
Figure 2.
Figure 2.
Function of mitochondrial regulation through Nrf2 signalling in CVD: ubiquitination regulation of Nrf2 is key to the cellular response to oxidative and electrophilic stresses. Nrf2 is polyubiquitinated by the Keap1–Cul3 complex in the basal state without oxidative or electrophilic stress. Cul3 is a ubiquitin ligase, while Keap1 is a substrate adapter. This polymerisation causes Nrf2 to be degraded by the proteasome. In the mitochondria, PGAM5 and Nrf2 bind to the monomer of the Keap1 dimer in a mutually exclusive manner. Nrf2 and PGAM5 regulate the activity of the Keap1–Cul3 E3 ubiquitin ligase, thus protecting Miro2 from abnormal degradation. In contrast, the activation of Nox2 induced by a high-fat diet induces ROS production, leading to calpain-1 mediated destruction of ERK5 and mitochondrial dysfunction by lowering the ERK5-MEf2-PGC α pathway. Similarly, acute exercise stress can upregulate the level of Nox4 in the myocardium and activate Nrf2/ARE signal transduction of Nrf2 target genes, such as TRXR2 and SOD2, which can reduce mitochondrial ROS and maintain cardiac performance. Nrf2, nuclear factor erythroid 2-related factor 2; Keap1, Kelch-like ECH-associated protein 1; Cul3, Cullin-3.
Figure 3.
Figure 3.
Regulation of Nrf2 in CVD.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Tune JD, Goodwill AG, Sassoon DJ, et al. . Cardiovascular consequences of metabolic syndrome. Transl Res. 2017;183:1–15. doi:10.1016/j.trsl.2017.01.001. - DOI - PMC - PubMed
    1. Kazamel M, Stino AM, Smith AG.. Metabolic syndrome and peripheral neuropathy. Muscle Nerve. 2021;63(3):285–293. doi:10.1002/mus.27086. - DOI - PubMed
    1. Kasper P, Martin A, Lang S, et al. . NAFLD and cardiovascular diseases: a clinical review. Clin Res Cardiol. 2021; 10(7):921–937. doi:10.1007/s00392-020-01709-7. - DOI - PMC - PubMed
    1. Caussy C, Aubin A, Loomba R.. The relationship between type 2 diabetes, NAFLD, and cardiovascular risk. Curr Diab Rep. 2021; 21(5):15. doi:10.1007/s11892-021-01383-7. - DOI - PMC - PubMed
    1. Silveira Rossi JL, Barbalho SM, Reverete de Araujo R, et al. . Metabolic syndrome and cardiovascular diseases: going beyond traditional risk factors. Diabetes Metab Res Rev. 2022;38(3):e3502. - PubMed

Publication types

MeSH terms

Grants and funding

The work was supported by the foundation of Key R&D plan of Sichuan Province (2019YFS0538); The project of 2020 High-level Overseas Chinese Talent Returning Funding; Overseas Famous Teacher Project of Guangdong Provincial Department of Science and Technology (2020A1414010311).
-