Inhibition of mitochondrial fission and NOX2 expression prevent nlrp3 inflammasome activation in the endothelium: The role of corosolic acid action in the amelioration of endothelial dysfunction
Abstract
AIMS: Corosolic acid (CRA) is a natural triterpenoid with antioxidative activity. This study was designed to elucidate the mechanism through which CRA protected vessel endothelial homeostasis by combating oxidative stress. RESULTS: In endothelial cells, CRA induced dynamin-related protein 1 (Drp1) phosphorylation at Ser637 and thus inhibited mitochondrial fission in response to oxidative stress. It promoted AMP-activated protein kinase (AMPK) activity in an LKB1-dependent manner, and silencing AMPK abrogated its inhibitory effect on Drp1 activation and mitochondrial fission. CRA inhibited the translocation of p47(phox) and p67(phox) and the overexpression of gp91(phox) induced by palmitate (PA), demonstrating its action in suppression of NOX2 activation. Drp1 knockdown reduced PA-induced gp91(phox) expression, while Drp1 induction was also diminished by gp91(phox) knockdown, suggesting the reciprocal relationship between NOX2 and Drp1. Knockdown Drp1 or gp91(phox) attenuated PA-induced NLRP3 induction and enhanced inhibitory effects of CRA. Oral administration of CRA in high-fat diet mice reproduced similar regulation in the aorta endothelium, further confirming its protection on endothelial homeostasis in vivo. INNOVATION: This study demonstrated that the defect in mitochondrial morphology is associated with the oxidative stress and NLRP3 inflammasome activation in the endothelium. Drp1 and NOX2 regulated each other and worked together to induce NLRP3 inflammasome activation, suggesting that modulation of Drp1 phosphorylation (Ser637) might be a potential therapeutic target for combating oxidative stress in vessel diseases. CONCLUSION: CRA prevented mitochondrial fission by regulation of Drp1 phosphorylation (Ser637) in an AMPK-dependent manner, and this action contributed to blocking NOX2 oxidase signaling and suppressing NLRP3 inflammasome activation in the endothelium. Antioxid. Redox Signal. 24, 893-908.
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Corosolic acid activated AMPK in a LKB1-dependent manner, and AMPK silencing abrogated its inhibitory effect on DRP1 activation and mitochondrial fission.
“CRA activated AMPK in a LKB1-dependent manner, and AMPK silencing abrogated its inhibitory effect on DRP1 activation and mitochondrial fission [141].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [141]
DRP1 knockdown attenuated PA-induced NOX2 activation, and knockdown of DRP1 or NOX2 suppressed PA-induced NLRP3 inflammatory effect and strengthened the inhibitory effects of corosolic acid.
“DRP1 knockdown attenuated PA-induced NOX2 activation, and knockdown of DRP1 or NOX2 suppressed PA-induced NACHT, LRR, and PYD domains-containing protein 3 inflammatory effect and, in the meantime, strengthened the inhibitory effects of CRA [141].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [141]
Corosolic acid alleviated endothelial inflammation in obesity by activating AMPK.
“Study showed that CRA alleviated endothelial inflammation in obesity by activating AMPK [141].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [141]
Corosolic acid prevented mitochondrial fission by regulating DRP1 phosphorylation at Ser637 in an AMPK-dependent manner, contributing to the blockage of NOX2-related oxidative stress and suppressing NLRP3 inflammasome in the endothelium.
“These data collectively demonstrated that CRA prevented mitochondrial fission by regulating DRP1 phosphorylation at Ser637 in an AMPK-dependent manner, contributing to the blockage of NOX2-related oxidative stress and suppressing NACHT, LRR, and PYD domains-containing protein 3 inflammasome in the endothelium [141].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [141]
Corosolic acid suppressed PA-induced NOX2 activation, which was revealed by the reduced migration of p47phox to cell membrane and inhibition of gp91phox expression.
“Concurrently, CRA suppressed PA-induced NOX2 activation, which was revealed by the reduced migration of p47phox to cell membrane and inhibition of gp91phox expression [141].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [141]
Corosolic acid suppressed DRP1 activation by inducing DRP1 phosphorylation at Ser637, thus inhibiting mitochondrial fission in endothelial cells in response to palmitate treatment.
“CRA suppressed DRP1 activation by inducing DRP1 phosphorylation at Ser637, thus inhibiting mitochondrial fission in ECs in response to palmitate (PA) treatment [141].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [141]
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- Authors
- Li, Y., Zhou, Z.-H., Chen, M.-H., Yang, J., Leng, J., Cao, G.-S., Xin, G.-Z., Liu, L.-F., Kou, J.-P., Liu, B.-L., Li, P., & Wen, X.-D.
- Affiliations
- China Pharmaceutical University (CN)
- China Pharmaceutical University
- Venue
- Antioxidants & Redox Signaling
- Publisher
- SAGE Publications
- Published
- 2016-06
- Volume
- 24
- Issue
- 16
- Pages
- 893-908
- ISSN
- 1523-0864 (ISSN-L)
- 1557-7716
- OpenAlex
- W2253297363
- Cited by
- 61
- References
- 41
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 3 · 2023: 6 · 2022: 5 · 2021: 6 · 2020: 10 · 2019: 4 · 2018: 5 · 2017: 9 · 2016: 2 · 2015: 1
- FWCI
- 3.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Antioxidants and Redox Signaling (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- corosolic acid, mitochondrial fission, Drp1 phosphorylation, NLRP3 inflammasome, NOX2, endothelial dysfunction, oxidative stress, AMPK, LKB1, palmitate, gp91phox, triterpenoids, high-fat diet, aorta
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, NADPH Oxidase 2, Animals, Cardiovascular Diseases, Cells, Cultured, Endothelium, Vascular, Male, Membrane Glycoproteins, Mice, Inbred ICR, Nuclear Proteins, Phosphoproteins, Triterpenes, Reactive Oxygen Species, Oxidative Stress, NADPH Oxidases, Protein Transport, Dynamins, Endothelial Cells, Mice, Rats, Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins, AMP-Activated Protein Kinases, Inflammasomes, Mitochondrial Dynamics
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