Microvascular and macrovascular diseases are important complications of metabolic diseases and affect the normal functioning of the human cardiovascular system. Endothelial dysfunction is the basic pathological tache of vascular diseases. This study aims to find out whether mangiferin can relieve endothelial dysfunction by inhibiting mitochondrial fission induced by endoplasmic reticulum stress. After being stimulated by palmitate, the expression of endoplasmic reticulum stress-related proteins Bip, p-PERK (RNA-like endoplasmic reticulum kinase) increased significantly. The endoplasmic reticulum stress was effectively inhibited after the treatment with mangiferin and the inhibition diminished after the knockout of AMPK (AMP-activated protein kinase) through AMPK siRNA interference, which demonstrated that AMPK was a key point for mangiferin action to exert its therapeutic effects. Under endoplasmic reticulum stress conditions, the influx of calcium ions from the endoplasmic reticulum into cytoplasm may lead to mitochondrial calcium ions overload and a large increase in mitochondrial ROS. As a result, mitochondrial fission was further promoted and apoptosis was induced. Mangiferin effectively improved the endothelial function by activating AMPK to inhibit the endoplasmic reticulum stress, maintaining the calcium homeostasis in mitochondria while inhibiting apoptosis by diminishing mitochondrial fission and ROS (Reactive Oxygen Specie) generation. In conclusion, mangiferin could maintain Ca2+ homeostasis in mitochondria under ER stress conditions, attenuate cell apoptosis induced by mitochondrial fission and ROS generation, and effectively improve the endothelial function by activating AMPK to inhibit endoplasmic reticulum stress.
| Published in | American Journal of Clinical and Experimental Medicine (Volume 5, Issue 5) |
| DOI | 10.11648/j.ajcem.20170505.12 |
| Page(s) | 162-172 |
| Creative Commons |
This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited. |
| Copyright |
Copyright © The Author(s), 2024. Published by Science Publishing Group |
Mangiferin, Endoplasmic Reticulum Stress, Mitochondrial Dysfunction, Endothelial Dysfunction
| [1] | Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease [J]. NATURE, 2006, 444(7121): 875-880. |
| [2] | Kaplon RE, Chung E, Reese L, et al. Activation of the Unfolded Protein Response in Vascular Endothelial Cells of Nondiabetic Obese Adults [J]. The Journal of Clinical Endocrinology & Metabolism, 2013, 98(9): E1505-E1509. |
| [3] | Appleton SL, Seaborn CJ, Visvanathan R, et al. Diabetes and Cardiovascular Disease Outcomes in the Metabolically Healthy Obese Phenotype: A cohort study [J]. DIABETES CARE, 2013, 36(8): 2388-2394. |
| [4] | Despres JP. Body Fat Distribution and Risk of Cardiovascular Disease: An Update [J]. CIRCULATION, 2012, 126(10): 1301-1313. |
| [5] | Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress [J]. CIRC RES, 2000. |
| [6] | Thomas Heitzer M, Titus Schlinzig B, Karoline Krohn B, et al. Endothelial Dysfunction, Oxidative Stress, and Risk of Cardiovascular Events in Patients With Coronary Artery Disease [J]. CIRCULATION, 2001, 104: 2673-2678. |
| [7] | Chambers JE, Marciniak SJ. Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease. 2. Protein misfolding and ER stress [J]. AJP: Cell Physiology, 2014, 307(8): C657-C670. |
| [8] | Fu S, Watkins SM, Hotamisligil GKS. The Role of Endoplasmic Reticulum in Hepatic Lipid Homeostasis and Stress Signaling [J]. CELL METAB, 2012, 15(5): 623-634. |
| [9] | Sovolyova N, Healy S, Samali A, et al. Stressed to death – mechanisms of ER stress-induced cell death [J]. BIOL CHEM, 2014, 395(1): 1-13. |
| [10] | Hall AR, Burke N, Dongworth RK, et al. Mitochondrial fusion and fission proteins: novel therapeutic targets for combating cardiovascular disease [J]. BRIT J PHARMACOL, 2014, 171(8): 1890-1906. |
| [11] | Orrenius S, Gogvadze V, Zhivotovsky B. Calcium and mitochondria in the regulation of cell death [J]. BIOCHEM BIOPH RES CO, 2015, 460(1): 72-81. |
| [12] | Contreras L, Drago I, Zampese E, et al. Mitochondria: The calcium connection [J]. Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2010, 1797(6-7): 607-618. |
| [13] | Pangare M, Makino A. Mitochondrial function in vascular endothelial cell in diabetes [J]. J. Smooth Muscle Res., 2012, 48(6): 1-26. |
| [14] | Pharmacol JC. Hyperglycemic Conditions Affect Shape and Ca2+ Homeostasis of Mitochondria in Endothelial Cells [J]. J Cardiovasc Pharmacol, 2004, 44: 423-436. |
| [15] | Dai DF, Rabinovitch PS, Ungvari Z. Mitochondria and Cardiovascular Aging [J]. CIRC RES, 2012, 110(8): 1109-1124. |
| [16] | Esper RJ, Nordaby RA, Vilariño JO, et al. Endothelial dysfunction: a comprehensive appraisal [J]. CARDIOVASC DIABETOL, 2006, 5: 4. |
| [17] | Pinton P, Giorgi C, Siviero R, et al. Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis [J]. ONCOGENE, 2008, 27(50): 6407-6418. |
| [18] | Kluck RM, Bossy-Wetzel E, Green DR, et al. The Release of Cytochrome c from Mitochondria: A Primary Site for Bcl-2 Regulation of Apoptosis [J]. SCIENCE, 1997, 275(5303): 1132-1136. |
| [19] | Zhou L, Pan Y, Chonan R, et al. Mitigation of Insulin Resistance by Mangiferin in a Rat Model of Fructose-Induced Metabolic Syndrome Is Associated with Modulation of CD36 Redistribution in the Skeletal Muscle [J]. J PHARMACOL EXP THER, 2015, 356(1): 74-84. |
| [20] | Song J, Li J, Hou F, et al. Mangiferin inhibits endoplasmic reticulum stress-associated thioredoxin-interacting protein/NLRP3 inflammasome activation with regulation of AMPK in endothelial cells [J]. METABOLISM, 2015, 64(3): 428-437. |
| [21] | Apontes P, Liu Z, Su K, et al. Mangiferin Stimulates Carbohydrate Oxidation and Protects Against Metabolic Disorders Induced by High-Fat Diets [J]. DIABETES, 2014, 63(11): 3626-3636. |
| [22] | Li J, Wang Y, Wang Y, et al. Pharmacological activation of AMPK prevents Drp1-mediated mitochondrial fission and alleviates endoplasmic reticulum stress-associated endothelial dysfunction [J]. J MOL CELL CARDIOL, 2015, 86: 62-74. |
| [23] | Toyama EQ, Herzig S, Courchet J, et al. Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress [J]. SCIENCE, 2016, 351(6270): 275-281. |
| [24] | Niu Y, Li S, Na L, et al. Mangiferin Decreases Plasma Free Fatty Acids through Promoting Its Catabolism in Liver by Activation of AMPK [J]. PLOS ONE, 2012. |
| [25] | Sellamuthu PS, Arulselvan P, Muniappan BP, et al. Mangiferin fromSalacia chinensis Prevents Oxidative Stress and Protects Pancreaticβ-Cells in Streptozotocin-Induced Diabetic Rats [J]. J MED FOOD, 2013, 16(8): 719-727. |
| [26] | Tsubaki M, Takeda T, Kino T, et al. Mangiferin suppresses CIA by suppressing the expression of TNF- α, IL-6, IL-1 β, and RANKL through inhibiting the activation of NF- κ B and ERK1/2 [J]. Am J Transl Res., 2015, 7(8): 1371-1381. |
| [27] | Go Khan S. Hotamisligil. Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease [J]. CELL, 2010, 140(6): 900-917. |
| [28] | Özcan U, Cao Q, Erkan Yilmaz, et al. Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes [J]. Science, 2004, 306(5695): 457-461. |
| [29] | Minamino T, Komuro I, Kitakaze M. Endoplasmic Reticulum Stress As a Therapeutic Target in Cardiovascular Disease [J]. CIRC RES, 2010, 107(9): 1071-1082. |
| [30] | Basha B, Samuel SM, Triggle CR, et al. Endothelial Dysfunction in Diabetes Mellitus: Possible Involvement of Endoplasmic Reticulum Stress? [J]. Experimental Diabetes Research, 2012, 2012: 1-14. |
| [31] | Kaplon RE, Chung E, Reese L, et al. Activation of the Unfolded Protein Response in Vascular Endothelial Cells of Nondiabetic Obese Adults [J]. The Journal of Clinical Endocrinology & Metabolism, 2013, 98(9): E1505-E1509. |
| [32] | Shenouda SM, Widlansky ME, Chen K, et al. Altered Mitochondrial Dynamics Contributes to Endothelial Dysfunction in Diabetes Mellitus [J]. CIRCULATION, 2011. |
| [33] | Chang C, Blackstone C. Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1 [J]. ANN NY ACAD SCI, 2010, 1201(1): 34-39. |
| [34] | Lee Y, Jeong S, Karbowski M, et al. Roles of the Mammalian Mitochondrial Fission and Fusion Mediators Fis1, Drp1, and Opa1 in Apoptosis [J]. MOL BIOL CELL, 2004, 15(11): 5001-5011. |
| [35] | Bianchi K, Rimessi A, Prandini A, et al. Calcium and mitochondria: mechanisms and functions of a troubled relationship [J]. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2004, 1742(1-3): 119-131. |
| [36] | Yu T, Sheu SS, Robotham JL, et al. Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species [J]. CARDIOVASC RES, 2008, 79(2): 341-351. |
| [37] | Huang F, Liu K, Du H, et al. Puerarin attenuates endothelial insulin resistance through inhibition of inflammatory response in an IKKβ/IRS-1-dependent manner [J]. BIOCHIMIE, 2012, 94(5): 1143-1150. |
| [38] | Okoshi R, Ozaki T, Yamamoto H, et al. Activation of AMP-activated Protein Kinase Induces p53-dependent Apoptotic Cell Death in Response to Energetic Stress [J]. J BIOL CHEM, 2008, 283(7): 3979-3987. |
| [39] | Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis [J]. NAT REV MOL CELL BIO, 2012, 13(4): 251-262. |
| [40] | Saha A, Coughlan K, Valentine R, et al. AMPK activation: a therapeutic target for type 2 diabetes?[J]. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 2014, 7: 241-253. |
| [41] | Langendorf CG, Kemp BE. Choreography of AMPK activation [J]. CELL RES, 2014, 25(1): 5-6. |
| [42] | Miller RA, Birnbaum MJ. An energetic tale of AMPK-independent effects of metformin [J]. J CLIN INVEST, 2010, 120(7): 2267-2270. |
APA Style
Yang Chen, Yu-peng Chen, Bao-lin Liu, Kang Liu, Fang Huang, et al. (2017). The Effect of Mangiferin on Improving Endothelial Dysfunction by Inhibiting Endoplasmic Reticulum Stress to Alleviate Mitochondrial Fission. American Journal of Clinical and Experimental Medicine, 5(5), 162-172. https://doi.org/10.11648/j.ajcem.20170505.12
ACS Style
Yang Chen; Yu-peng Chen; Bao-lin Liu; Kang Liu; Fang Huang, et al. The Effect of Mangiferin on Improving Endothelial Dysfunction by Inhibiting Endoplasmic Reticulum Stress to Alleviate Mitochondrial Fission. Am. J. Clin. Exp. Med. 2017, 5(5), 162-172. doi: 10.11648/j.ajcem.20170505.12
AMA Style
Yang Chen, Yu-peng Chen, Bao-lin Liu, Kang Liu, Fang Huang, et al. The Effect of Mangiferin on Improving Endothelial Dysfunction by Inhibiting Endoplasmic Reticulum Stress to Alleviate Mitochondrial Fission. Am J Clin Exp Med. 2017;5(5):162-172. doi: 10.11648/j.ajcem.20170505.12
Share This Article
Twitter
Linked In
Facebook
Copy
Download@article{10.11648/j.ajcem.20170505.12,
author = {Yang Chen and Yu-peng Chen and Bao-lin Liu and Kang Liu and Fang Huang and Zhi-xia Qiu},
title = {The Effect of Mangiferin on Improving Endothelial Dysfunction by Inhibiting Endoplasmic Reticulum Stress to Alleviate Mitochondrial Fission},
journal = {American Journal of Clinical and Experimental Medicine},
volume = {5},
number = {5},
pages = {162-172},
doi = {10.11648/j.ajcem.20170505.12},
url = {https://doi.org/10.11648/j.ajcem.20170505.12},
eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ajcem.20170505.12},
abstract = {Microvascular and macrovascular diseases are important complications of metabolic diseases and affect the normal functioning of the human cardiovascular system. Endothelial dysfunction is the basic pathological tache of vascular diseases. This study aims to find out whether mangiferin can relieve endothelial dysfunction by inhibiting mitochondrial fission induced by endoplasmic reticulum stress. After being stimulated by palmitate, the expression of endoplasmic reticulum stress-related proteins Bip, p-PERK (RNA-like endoplasmic reticulum kinase) increased significantly. The endoplasmic reticulum stress was effectively inhibited after the treatment with mangiferin and the inhibition diminished after the knockout of AMPK (AMP-activated protein kinase) through AMPK siRNA interference, which demonstrated that AMPK was a key point for mangiferin action to exert its therapeutic effects. Under endoplasmic reticulum stress conditions, the influx of calcium ions from the endoplasmic reticulum into cytoplasm may lead to mitochondrial calcium ions overload and a large increase in mitochondrial ROS. As a result, mitochondrial fission was further promoted and apoptosis was induced. Mangiferin effectively improved the endothelial function by activating AMPK to inhibit the endoplasmic reticulum stress, maintaining the calcium homeostasis in mitochondria while inhibiting apoptosis by diminishing mitochondrial fission and ROS (Reactive Oxygen Specie) generation. In conclusion, mangiferin could maintain Ca2+ homeostasis in mitochondria under ER stress conditions, attenuate cell apoptosis induced by mitochondrial fission and ROS generation, and effectively improve the endothelial function by activating AMPK to inhibit endoplasmic reticulum stress.},
year = {2017}
}
TY - JOUR T1 - The Effect of Mangiferin on Improving Endothelial Dysfunction by Inhibiting Endoplasmic Reticulum Stress to Alleviate Mitochondrial Fission AU - Yang Chen AU - Yu-peng Chen AU - Bao-lin Liu AU - Kang Liu AU - Fang Huang AU - Zhi-xia Qiu Y1 - 2017/08/31 PY - 2017 N1 - https://doi.org/10.11648/j.ajcem.20170505.12 DO - 10.11648/j.ajcem.20170505.12 T2 - American Journal of Clinical and Experimental Medicine JF - American Journal of Clinical and Experimental Medicine JO - American Journal of Clinical and Experimental Medicine SP - 162 EP - 172 PB - Science Publishing Group SN - 2330-8133 UR - https://doi.org/10.11648/j.ajcem.20170505.12 AB - Microvascular and macrovascular diseases are important complications of metabolic diseases and affect the normal functioning of the human cardiovascular system. Endothelial dysfunction is the basic pathological tache of vascular diseases. This study aims to find out whether mangiferin can relieve endothelial dysfunction by inhibiting mitochondrial fission induced by endoplasmic reticulum stress. After being stimulated by palmitate, the expression of endoplasmic reticulum stress-related proteins Bip, p-PERK (RNA-like endoplasmic reticulum kinase) increased significantly. The endoplasmic reticulum stress was effectively inhibited after the treatment with mangiferin and the inhibition diminished after the knockout of AMPK (AMP-activated protein kinase) through AMPK siRNA interference, which demonstrated that AMPK was a key point for mangiferin action to exert its therapeutic effects. Under endoplasmic reticulum stress conditions, the influx of calcium ions from the endoplasmic reticulum into cytoplasm may lead to mitochondrial calcium ions overload and a large increase in mitochondrial ROS. As a result, mitochondrial fission was further promoted and apoptosis was induced. Mangiferin effectively improved the endothelial function by activating AMPK to inhibit the endoplasmic reticulum stress, maintaining the calcium homeostasis in mitochondria while inhibiting apoptosis by diminishing mitochondrial fission and ROS (Reactive Oxygen Specie) generation. In conclusion, mangiferin could maintain Ca2+ homeostasis in mitochondria under ER stress conditions, attenuate cell apoptosis induced by mitochondrial fission and ROS generation, and effectively improve the endothelial function by activating AMPK to inhibit endoplasmic reticulum stress. VL - 5 IS - 5 ER -
Information
Email: