Mitochondria-targeted esculetin alleviates mitochondrial dysfunction by AMPK-mediated nitric oxide and SIRT3 regulation in endothelial cells: Potential implications in atherosclerosis
Open accessAbstract
Mitochondria-targeted compounds are emerging as a new class of drugs that can potentially alter the pathophysiology of those diseases where mitochondrial dysfunction plays a critical role. We have synthesized a novel mitochondria-targeted esculetin (Mito-Esc) with an aim to investigate its effect during oxidative stress-induced endothelial cell death and angiotensin (Ang)-II-induced atherosclerosis in ApoE(-/-) mice. Mito-Esc but not natural esculetin treatment significantly inhibited H2O2- and Ang-II-induced cell death in human aortic endothelial cells by enhancing NO production via AMPK-mediated eNOS phosphorylation. While L-NAME (NOS inhibitor) significantly abrogated Mito-Esc-mediated protective effects, Compound c (inhibitor of AMPK) significantly decreased Mito-Esc-mediated increase in NO production. Notably, Mito-Esc promoted mitochondrial biogenesis by enhancing SIRT3 expression through AMPK activation; and restored H2O2-induced inhibition of mitochondrial respiration. siSIRT3 treatment not only completely reversed Mito-Esc-mediated mitochondrial biogenetic marker expressions but also caused endothelial cell death. Furthermore, Mito-Esc administration to ApoE(-/-) mice greatly alleviated Ang-II-induced atheromatous plaque formation, monocyte infiltration and serum pro-inflammatory cytokines levels. We conclude that Mito-Esc is preferentially taken up by the mitochondria and preserves endothelial cell survival during oxidative stress by modulating NO generation via AMPK. Also, Mito-Esc-induced SIRT3 plays a pivotal role in mediating mitochondrial biogenesis and perhaps contributes to its anti-atherogenic effects.
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Mitochondria-targeted esculetin greatly alleviated angiotensin II-induced monocyte infiltration, atherosclerotic plaque formation, and serum pro-inflammatory cytokine production in apolipoprotein E KO mice.
“Mitochondria-targeted esculetin, capable of scavenging mitochondrial ROS, greatly alleviated angiotensin II-induced monocyte infiltration, atherosclerotic plaque formation, and serum pro-inflammatory cytokine production in apolipoprotein E KO mice [131].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [131]
In cultured human aortic endothelial cells, mitochondria-targeted esculetin significantly inhibited angiotensin II-induced cell death via enhancement of NO production via AMPK-eNOS signaling.
“In cultured human aortic endothelial cells, mechanistic study showed that mitochondria-targeted esculetin significantly inhibited angiotensin II-induced cell death via enhancement of NO production via AMPK–eNOS signaling [131].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [131]
Anti-atherogenic effects of mitochondria-targeted esculetin are likely owing to promotion of mitochondrial biogenesis through AMPK-SIRT3 signaling.
“Notably, the anti-atherogenic effects of mitochondria-targeted esculetin are likely owing to the promotion of mitochondrial biogenesis through AMPK–SIRT3 signaling [131].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [131]
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References 54 · Cited by 62
- Authors
- Karnewar, S., Vasamsetti, S. B., Gopoju, R., Kanugula, A. K., Ganji, S. K., Prabhakar, S., Rangaraj, N., Tupperwar, N., Kumar, J. M., & Kotamraju, S.
- Affiliations
- Indian Institute of Chemical Technology (IN)
- Centre for Cellular and Molecular Biology (IN)
- Corresponding author
- Kumar, Jerald Mahesh
- Kotamraju, Srigiridhar
- ORCID
- Venue
- Scientific Reports
- Published
- 2016-04-11
- Volume
- 6
- Issue
- 1
- Pages
- 24108-24108
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4827087
- OpenAlex
- W2320530511
- Cited by
- 62
- References
- 54
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 5 · 2023: 5 · 2022: 5 · 2021: 4 · 2020: 7 · 2019: 8 · 2018: 11 · 2017: 8 · 2016: 1
- FWCI
- 7.52
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Greater South Information System
- Funders
- Indian Council of Medical Research
- Council of Scientific and Industrial Research, India (CSC 0111)
- China Scholarship Council
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- esculetin, mitochondrial dysfunction, AMPK, nitric oxide, SIRT3, endothelial cell death, oxidative stress, angiotensin II, atherosclerosis, mitochondrial biogenesis, endothelial nitric oxide synthase, ApoE-deficient mice, atherosclerotic plaque, monocyte infiltration, inflammatory cytokines
- MeSH terms
- Angiotensin II, Animals, Antioxidants, Aorta, Apolipoproteins E, Cell Survival, Cells, Cultured, Humans, Hydrogen Peroxide, Male, Mitochondria, Nitric Oxide, Oxygen Consumption, Phosphorylation, Umbelliferones, Apoptosis, Mice, Knockout, Oxidative Stress, Microscopy, Confocal, NG-Nitroarginine Methyl Ester, RNA Interference, RNA, Small Interfering, Endothelial Cells, Atherosclerosis, Mice, Nitric Oxide Synthase Type III, Membrane Potential, Mitochondrial, AMP-Activated Protein Kinases, Sirtuin 3
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