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Review
. 2021 Aug 14;34(2):113-118.
doi: 10.4103/tcmj.tcmj_83_21. eCollection 2022 Apr-Jun.

The potential of using itaconate as treatment for inflammation-related heart diseases

Hui-Chen Ku  1 , Ta-Chung Shen  2 , Ching-Feng Cheng  1   3   4
Affiliations
Review

The potential of using itaconate as treatment for inflammation-related heart diseases

Hui-Chen Ku et al. Tzu Chi Med J. .

Abstract

Intracellular metabolites can cause critical changes in biological functions. Itaconate is perhaps the most fascinating substance in macrophages. Lipopolysaccharide can activate aconitate decarboxylase 1 and induces the generation of itaconate from the tricarboxylic acid cycle by decarboxylation of cis-aconitate. It has been reported that itaconate has beneficial effects on inflammation and oxidation. The mechanisms involved in these effects include the suppression of succinate dehydrogenase, the activation of nuclear factor E2-related factor 2 by alkylation of Kelch-like ECH-associated protein 1, suppression of aerobic glycolysis through regulation of glyceraldehyde-3-phosphate dehydrogenase and fructose-bisphosphate aldolase A, and suppression of IκBζ translation through activating transcription factor 3 activation. All of these findings elucidated the possible therapeutic implications of itaconate in inflammation-related diseases. In this review, we highlight that itaconate is a crucial molecule of the immunomodulatory response in macrophages and can regulate between immune response and cardiovascular metabolism. Furthermore, these discoveries suggest that itaconate is a very novel therapeutic molecule for the treatment of inflammation-related heart diseases.

Keywords: Activating transcription factor 3; Inflammation; Itaconate; Nuclear factor erythroid 2-related factor 2; Succinate dehydrogenase.

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Conflict of interest statement

Dr. Ching-Feng Cheng, an editorial board member at Tzu Chi Medical Journal, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.

Figures

Figure 1
Figure 1
Itaconate biogenesis and metabolism. (a) Inflammatory stimuli activate aconitate decarboxylase 1 expression, which induces the production of itaconate by decarboxylation of cis-aconitate in the tricarboxylic acid cycle of the mitochondrial matrix. Citrate lyase subunit beta-like catalyzies citramalyl-CoA to pyruvate and acetyl-CoA. (b) Chemical structures of itaconate, dimethyl itaconate and 4-octyl itaconate
Figure 2
Figure 2
Itaconate suppresses inflammatory and oxidative signaling pathways. Itaconate is produced in macrophages activated by lipopolysaccharide through upregulating aconitate decarboxylase 1 expression. Increased itaconate activates the nuclear factor erythroid 2-related factor 2 signaling through alkylation of Kelch-like ECH-associated protein 1, which activates the transcription of HO-1 and glutathione. In addition, itaconate can suppress succinate dehydrogenase and decrease reactive oxygen species generation and interleukin-1β secretion. Itaconate increases activating transcription factor 3 expression, which directly suppresses IκBζ expression and results in reducing interleukin interleukin-6. Furthermore, itaconate promotes alkylation of glyceraldehyde-3-phosphate dehydrogenase and aldolase A to suppress glycolysis, thus alleviating the inflammation
Figure 3
Figure 3
The summarized graphical abstract of related pathways involved in itaconate regulation of inflammation. Lipopolysaccharide can activate aconitate decarboxylase 1 and induces the production of itaconate from the tricarboxylic acid cycle. Itaconate exerts anti-inflammatory effects by suppression of succinate dehydrogenase, Kelch-like ECH-associated protein 1, glyceraldehyde-3-phosphate dehydrogenase, and aldolase A, but activation of activating transcription factor 3
See this image and copyright information in PMC

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