Cordycepin Attenuates Palmitic Acid-Induced Inflammation and Apoptosis of Vascular Endothelial Cells through Mediating PI3K/Akt/eNOS Signaling Pathway
Abstract
A well-known medicinal mushroom in the field of traditional Chinese medicine, Cordyceps sinensis, is a rare natural-occurring entomopathogenic fungus, and it typically grows at high altitudes on the plateau of the Himalayan. Previous studies indicated that cordycepin, the main bioactive chemical of Cordyceps sinensis, has very potent anticancer, anti-oxidant and anti-inflammatory activities. However, its protective effects against atherosclerotic changes in vascular endothelial cells have not been fully elucidated. In this study, we showed that pretreatment with cordycepin significantly attenuated palmitic acid (PA)-induced cytotoxicity, reactive oxygen species (ROS) generation, and inflammatory responses. We found that PA decreased phosphorylation of Akt, eNOS, and bioavailability of nitric oxide (NO), which in turn activated NF-B and the downstream inflammatory responses. All these detrimental events were markedly blocked by pretreatment with cordycepin. Moreover, cordycepin ameliorated destabilization of mitochondrial permeability, cytosolic calcium rises, and apoptotic features caused by PA. In addition, all these anti-inflammatory and anti-apoptosis effects of cordycepin were found to be inhibited by the PI3K and eNOS inhibitor, suggesting that its anti-atherosclerotic effects may partially be mediated by the PI3K/Akt/eNOS signaling pathway.
References
- Free fatty acids trigger apoptosis and inhibit cell cycle progression in human vascular endothelial cells. FASEB J. 18: 146–148, 2004. Crossref, Medline, ISI, Google Scholar .
- Withaferin A protects against palmitic acid-induced endothelial insulin resistance and dysfunction through suppression of oxidative stress and inflammation. Sci. Rep. 6: 27236, 2016. Crossref, Medline, ISI, Google Scholar .
- Effect of augmented glycation in mobilization of plasma free fatty acids in type 2 diabetes mellitus. Diabetes Metab. Syndr. 14: 1385–1389, 2020. Crossref, Medline, ISI, Google Scholar .
- Palmitic acid-induced autophagy increases reactive oxygen species via the Ca/PKC/NOX4 pathway and impairs endothelial function in human umbilical vein endothelial cells. Exp. Ther. Med. 17: 2425–2432, 2019. Medline, ISI, Google Scholar .
- Plasma metabolomics reveals biomarkers of the atherosclerosis. J. Sep. Sci. 33: 2776–2783, 2010. Crossref, Medline, ISI, Google Scholar .
- Cordycepin-induced apoptosis and autophagy in breast cancer cells are independent of the estrogen receptor. Toxicol. Appl. Pharmacol. 257: 165–173, 2011. Crossref, Medline, ISI, Google Scholar .
- Anti-inflammatory effects of cordycepin in lipopolysaccharide-stimulated RAW 264.7 macrophages through toll-like receptor 4-mediated suppression of mitogen-activated protein kinases and NF-B signaling pathways. Drug Des. Devel. Ther. 8: 1941–1953, 2014. Crossref, Medline, ISI, Google Scholar .
- Protective effect of cordyceps militaris against high glucose-induced oxidative stress in human umbilical vein endothelial cells. Food Chem. 129: 871–876, 2011. Crossref, Medline, ISI, Google Scholar .
- Palmitoleic acid has stronger anti-inflammatory potential in human endothelial cells compared to oleic and palmitic acids. Mol. Nutr. Food Res. 62: e1800322, 2018. Crossref, Medline, ISI, Google Scholar .
- Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. J. Immunol. 141: 2407–2412, 1988. Crossref, Medline, ISI, Google Scholar .
- Oxidative stress in cardiovascular diseases. Antioxidants 9: 864, 2020. Crossref, ISI, Google Scholar .
- Palmitate-induced endothelial dysfunction is attenuated by cyanidin-3-O-glucoside through modulation of Nrf2/Bach1 and NF-B pathways. Toxicol. Lett. 239: 152–160, 2015. Crossref, Medline, ISI, Google Scholar .
- Dickkopf-1/cysteine-rich angiogenic inducer 61 axis mediates palmitic acid-induced inflammation and apoptosis of vascular endothelial cells. Mol. Med. Rep. 23: 122, 2021. Crossref, Medline, ISI, Google Scholar .
- Inflammatory chemokines in atherosclerosis. Cells 10: 226, 2021. Crossref, Medline, ISI, Google Scholar .
- Double knockout of Akt2 and AMPK accentuates high fat diet-induced cardiac anomalies through a cGAS-STING-mediated mechanism. Biochim. Biophys. Acta Mol. Basis Dis. 1866: 165855, 2020. Crossref, Medline, ISI, Google Scholar .
- Resveratrol analog piceatannol restores the palmitic acid-induced impairment of insulin signaling and production of endothelial nitric oxide via activation of anti-inflammatory and antioxidative heme oxygenase-1 in human endothelial cells. Mol. Med. Rep. 12: 937–944, 2015. Crossref, Medline, ISI, Google Scholar .
- Inflammatory response of human coronary artery endothelial cells to saturated long-chain fatty acids. Microvasc. Res. 81: 52–59, 2011. Crossref, Medline, ISI, Google Scholar .
- Eicosapentaenoic acid protects against palmitic acid-induced endothelial dysfunction via activation of the AMPK/eNOS pathway. Int. J. Mol. Sci. 15: 10334–10349, 2014. Crossref, Medline, ISI, Google Scholar .
- A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin. Sci. Rep. 9: 15760, 2019. Crossref, Medline, ISI, Google Scholar .
- Ophiopogonin D alleviates diabetic myocardial injuries by regulating mitochondrial dynamics. J. Ethnopharmacol. 271: 113853, 2021. Crossref, Medline, ISI, Google Scholar .
- Apoptotic cell death in atherosclerosis. Curr. Opin. Lipidol. 14: 469–475, 2003. Crossref, Medline, ISI, Google Scholar .
- Interaction of TPPP3 with VDAC1 promotes endothelial injury through activation of reactive oxygen species. Oxid. Med. Cell. Longev. 2020: 5950195, 2020. Crossref, Medline, ISI, Google Scholar .
- Protective effects of Danzhi jiangtang capsule on vascular endothelial damages induced by high-fat diet and palmitic acid. Biomed. Pharmacother. 107: 1631–1640, 2018. Crossref, Medline, ISI, Google Scholar .
- Nitrosation and oxidation in the regulation of gene expression. FASEB J. 14: 1889–1900, 2000. Crossref, Medline, ISI, Google Scholar .
- Endothelial dysfunction in neuroprogressive disorders-causes and suggested treatments. BMC Med. 18: 305, 2020. Crossref, Medline, ISI, Google Scholar .
- Aspirin prevents resistin-induced endothelial dysfunction by modulating AMPK, ROS, and Akt/eNOS signaling. J. Vasc. Surg. 55: 1104–1115, 2012. Crossref, Medline, ISI, Google Scholar .
- Epigallocatechin gallate reduces homocysteine-caused oxidative damages through modulation SIRT1/AMPK pathway in endothelial cells. Am. J. Chin. Med. 49: 113–129, 2021. Link, ISI, Google Scholar .
- p66SHC promotes T cell apoptosis by inducing mitochondrial dysfunction and impaired Ca2+ homeostasis. Cell Death Differ. 14: 338–347, 2007. Crossref, Medline, ISI, Google Scholar .
- Bioactive principles from Cordyceps sinensis: A potent food supplement - A review. J. Funct. Foods 5: 1013–1030, 2013. Crossref, Medline, ISI, Google Scholar .
- Cordyceps sinensis increases hypoxia tolerance by inducing heme oxygenase-1 and metallothionein via Nrf2 activation in human lung epithelial cells. Biomed. Res. Int. 2013: 569206, 2013. Crossref, Medline, ISI, Google Scholar .
- Cordyceps militaris improves the survival of Dahl salt-sensitive hypertensive rats possibly via influences of mitochondria and autophagy functions. Heliyon 3: e00462, 2017. Crossref, Medline, ISI, Google Scholar .
- Pharmacological and therapeutic potential of Cordyceps with special reference to Cordycepin. 3 Biotech. 4: 1–12, 2014. Crossref, Medline, Google Scholar .
- Cordycepin: A bioactive metabolite with therapeutic potential. Life Sci. 93: 863–869, 2013. Crossref, Medline, ISI, Google Scholar .
- Cordycepin ameliorates cardiac hypertrophy via activating the AMPKalpha pathway. J. Cell Mol. Med. 23: 5715–5727, 2019. Crossref, Medline, ISI, Google Scholar .
- Palmitic acid decreases phosphorylation of eNOS Ser1177 by activating protein phosphatase 2C (PP2C) of human umbilical vein endothelial cells]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 36: 520–526, 2020. Medline, Google Scholar .
- The cordycepin derivative IMM-H007 improves endothelial dysfunction by suppressing vascular inflammation and promoting AMPK-dependent eNOS activation in high-fat diet-fed ApoE knockout mice. Eur. J. Pharmacol. 852: 167–178, 2019. Crossref, Medline, ISI, Google Scholar .
- Palmitic acid exerts pro-inflammatory effects on vascular smooth muscle cells by inducing the expression of C-reactive protein, inducible nitric oxide synthase and tumor necrosis factor-. Int. J. Mol. Med. 34: 1706–1712, 2014a. Crossref, Medline, ISI, Google Scholar .
- Cordycepin activates AMP-activated protein kinase (AMPK) via interaction with the 1 subunit. J. Cell. Mol. Med. 18: 293–304, 2014b. Crossref, Medline, ISI, Google Scholar .
- Simultaneous activation of Erk1/2 and Akt signaling is critical for formononetin-induced promotion of endothelial function. Front. Pharmacol. 11: 608518, 2020. Crossref, Medline, ISI, Google Scholar .
- Serum free fatty acid pattern and risk of myocardial infarction: A case-control study. J. Intern. Med. 251: 19–28, 2002. Crossref, Medline, ISI, Google Scholar .
- Src-mediated Tyr353 phosphorylation of IP3R1 promotes its stability and causes apoptosis in palmitic acid-treated hepatocytes. Exp. Cell Res. 399: 112438, 2021. Crossref, Medline, ISI, Google Scholar .
- Cordycepin inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)- production via activating amp-activated protein kinase (AMPK) signaling. Int. J. Mol. Sci. 15: 12119–12134, 2014. Crossref, Medline, ISI, Google Scholar .
- Overexpression of microRNA155 alleviates palmitate-induced vascular endothelial cell injury in human umbilical vein endothelial cells by negatively regulating the Wnt signaling pathway. Mol. Med. Rep. 20: 3527–3534, 2019. Medline, ISI, Google Scholar .
- The mitochondrial permeability transition. Biochim. Biophys. Acta 1241: 139–176, 1995. Crossref, Medline, ISI, Google Scholar .
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