Curcumin protects human umbilical vein endothelial cells against high oxidized low density lipoprotein-induced lipotoxicity and modulates autophagy

Document Type : Original Article

Authors

1 Department of Immunology and Microbiology, School of Basic Medical Sciences, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, P.R. China

2 Department of Experimental Center, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, P.R. China

3 Department of Cardiovascular Medicine, Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550025, P.R. China

4 Department of Morphology Laboratory, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, P.R. China

Abstract

Objective(s): Endothelial dysfunction is a precursor of cardiovascular disease, and protecting endothelial cells from damage is a treatment strategy for atherosclerosis (AS). Curcumin, a natural polyphenolic compound, has been shown to protect endothelial cells from dysfunction. In the present study, we investigated whether curcumin could ameliorate high oxidized low-density lipoprotein (ox‐LDL)-induced endothelial lipotoxicity by inducing autophagy in human umbilical vein endothelial cells (HUVECs).
Materials and Methods: HUVECs were treated with 50 μM high ox‐LDL alone or in combination with 5 μM curcumin for 24 hr. Cell viability and function were assessed by the cell counting kit-8 (CCK-8) assay, tube formation assay and cell migration experiments. Oil red O staining was used to detect lipid droplet accumulation in HUVECs. The change in reactive oxygen species (ROS) levels in HUVECs was measured with the probe DCFH-DA. Quantitative real-time PCR (qPCR) and Western blotting were used to evaluate the mRNA and protein levels of several inflammatory and autophagy-related factors.
Results: Cell viability was restored, tube formation and migration ability were increased, and lipid accumulation, oxidative stress and inflammatory responses were decreased in the curcumin-treated group compared with the high ox‐LDL group. Furthermore, high ox‐LDL inhibited HUVEC autophagy, and this effect was reversed by curcumin. Moreover, curcumin regulated the expression of several key proteins involved in the AMPK/mTOR/p70S6K signaling pathway.
Conclusion: Our findings suggest that curcumin is able to reduce endothelial lipotoxicity and modulate autophagy and that the AMPK/mTOR/p70S6K pathway might play a key role in these effects.

Keywords

References

1. Endemann DH, Schiffrin EL. Endothelial dysfunction. J Am Soc Nephrol 2004; 15: 1983-1992.
2. Bernhard D, Wang XL. Smoking, oxidative stress and cardiovascular diseases-do anti-oxidative therapies fail? Curr Med Chem 2007; 14: 1703-1712.
3. Nicolls MR, Haskins K, Flores SC. Oxidant stress, immune dysregulation, and vascular function in type I diabetes. Antioxid Redox Signal 2007; 9: 879‐889.
4. Buday A, Orsy P, Godó M, Mózes M, Kökény G, Lacza Z, et al. Elevated systemic TGF-beta impairs aortic vasomotor function through activation of NADPH oxidase-driven superoxide production and leads to hypertension, myocardial remodeling, and increased plaque formation in apoE(-/-) mice. Am J Physiol Heart Circ Physiol 2010; 299: H386-395.
5. Stary HC. Natural history and histological classification of atherosclerotic lesions:an update. Arterioscler Thromb Vasc Biol 2000; 20: 1177–1178.
6. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20: 1262–1275.
7. Simionescu N, Vasile E, Lupu F, Popescu G, Simionescu M. Prelesional events in atherogenesis. Accumulation of extracellular cholesterol-rich liposomes in the arterial intima and cardiac valves of the hyperlipidemic rabbit. Am J Pathol 1986; 123: 109–125.
8. Ross R, Glomset JA. Atherosclerosis and the arterial smooth muscle cell: Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science 1973; 180: 1332–1339.
9. Ross R, Glomset JA. The pathogenesis of atherosclerosis (first of two parts). N Engl J Med 1976; 295: 369–377.
10. Zhang X, Han X, Zhang P, Zhou T, Chen Y, Jin J, et al. Morin attenuates oxidized low-density lipoprotein-mediated injury by inducing autophagy via activating AMPK signalling in HUVECs. Clin Exp Pharmacol Physiol 2019; 46: 1053-1060.
11. Luo RX, Li LZ, Liu XH, Yuan YJ, Zhu WZ, Li L, et al. Mesenchymal stem cells alleviate palmitic acid-induced endothelial-to-mesenchymal transition by suppressing endoplasmic reticulum stress. Am J Physiol Endocrinol Metab 2010; 319: E961-980.
12. Yamagata K, Yamori Y. Inhibition of endothelial dysfunction by dietary flavonoids and preventive effects against cardiovascular disease. J Cardiovasc Pharmacol 2020; 75: 1-9.
13. Tomonori A, Daisuke S, Noriaki T, Seiji T, Eiichiro Y, Yasuhiro I, et al. Effects of the mean amplitude of glycemic excursions and vascular endothelial dysfunction on cardiovascular events in nondiabetic patients with coronary artery disease. J Am Heart Assoc 2017; 6: e004841.
14. Yang Z, Klionsky DJ. Eaten alive: a history of macroautophagy. Nat Cell Biol 2010; 12: 814‐822.
15. Puleston DJ, Simon AK. Autophagy in the immune system. Immunology 2014; 141: 1‐8.
16. Ouimet M. Autophagy in obesity and atherosclerosis: interrelationships between cholesterol homeostasis, lipoprotein metabolism and autophagy in macrophages and other systems. Biochim Biophys Acta 2013; 183: 1124‐1133.
17. Muller C, Salvayre R, Negre‐Salvayre A, Vindis C. Oxidized LDLs trigger endoplasmic reticulum stress and autophagy: prevention by HDLs. Autophagy 2011; 7: 541‐543.
18. Perrotta I, Aquila S. The role of oxidative stress and autophagy in atherosclerosis. Oxid Med Cell Longev 2015; 2015: 130315.
19. Le Guezennec X, Brichkina A, Huang YF, Kostromina E, Han W, Bulavin DV. Wip1-dependent regulation of autophagy, obesity, and atherosclerosis. Cell Metab 2012; 16: 68-80.
20. Shan R, Liu N, Yan Y, Liu B. Apoptosis, autophagy and atherosclerosis: relationships and the role of Hsp27. Pharmacol Res 2020; 11: 105169.
21. Peng S, Xu LW, Che XY, Xiao QQ, Pu J, Shao Q, et al. Atorvastatin inhibits inflammatory response, attenuates lipid deposition, and improves the stability of vulnerable atherosclerotic plaques by modulating autophagy. Front Pharmacol 2018; 9: 438.
22. Zhang N, Zhi XY, Zhao J, Wei JL, Li JP, Yang HF. Mesoporous silica induces hippocampal neurons cell autophagy through AMPK/mTOR/P70S6K signaling pathway. Environ Toxicol 2020; 35: 176-187.
23. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13: 132‐141.
24. Zhang P, Liu X, Li H, Chen Z, Yao X, Jin J, et al. TRPC5‐induced autophagy promotes drug resistance in breast carcinoma via CaMKKbeta/AMPKalpha/mTOR pathway. Sci Rep 2017; 7: 3158.
25. Kim Y C, Guan K L. mTOR: a pharmacologic target for autophagy regulation. J Clin Invest 2015; 125: 25-32.
26. Sun XW, Wang DY, Zhang TT, Lu XJ, Duan FF, Ju LI, et al. Eugenol attenuates cerebral ischemia-reperfusion injury by enhancing autophagy via AMPK-mTOR-P70S6K pathway. Front Pharmacol 2020; 11: 84-95.
27. Wang P, Jiang LZ, Zhou N, Zhou H, Liu HZ, Zhao WR, et al. Resveratrol ameliorates autophagic flux to promote functional recovery in rats after spinal cord injury. Oncotarget 2018; 9: 8427-8440.
28. Mohammadian HS, Karimzadeh MR, Azhdari S, Vahedi P, Abdollahi E, Momtazi-Borojeni AA. Modulatory effects of curcumin on the atherogenic activities of inflammatory monocytes: Evidence from in vitro and animal models of human atherosclerosis. Biofactors 2020; 46: 341-355.
29. Zhou YY, Zhang TT, Wang XF, Wei XW, Chen YZ, Guo LY, et al. Curcumin modulates macrophage polarization through the inhibition of the Toll-like receptor 4 expression and its signaling pathways. Cell Physiol Biochem 2015; 36: 631-641.
30. Batra H, Pawar S, Bahl D. Curcumin in combination with anti-cancer drugs: A nanomedicine review. Pharmacol Res 2019; 139: 91-105.
31. Zhang S, Zou J, Li P, Zheng X, Feng D. Curcumin protects against atherosclerosis in apolipoprotein E-Knockout mice by inhibiting Toll-like receptor 4 expression. J Agric Food Chem 2018; 66: 449-456.
32. Zou J, Zhang S, Li P, Zheng X, Feng D. Supplementation with curcumin inhibits intestinal cholesterol absorption and prevents atherosclerosis in high-fat diet-fed apolipoprotein E knockout mice. Nutr Res 2018; 56: 32-40.
33. Shakeri A, Cicero AFG, Panahi Y, Mohajeri M, Sahebkar A. Curcumin: A naturally occurring autophagy modulator. J Cell Physiol 2019; 234: 5643-5654.
34. Carmeliet P. Angiogenesis in life, disease and medicine. Nature 2005; 438: 932-936.
35. Yamagata K. Docosahexaenoic acid regulates vascular endothelial cell function and prevents cardiovascular disease. Lipids Health Dis 2017; 16: 118.
36. Wang Z, Wang Y, Chen Y, Lv J. The IL-24 gene protects human umbilical vein endothelial cells against H₂O₂-induced injury and may be useful as a treatment for cardiovascular disease. Int J Mol Med 2016; 37: 581-592.
37. Guo N, Chen F, Zhou J, Fang Y, Li H, Luo Y, et al. Curcumin attenuates rapamycin-induced cell injury of vascular endothelial cells. J Cardiovasc Pharmacol 2015; 66: 338-346.
38. Li J, Luo M, Xie N, Wang J, Chen L. Curcumin protects endothelial cells against homocysteine induced injury through inhibiting inflammation. Am J Transl Res 2016; 8: 4598-4604.
39. Luo R, Zhao L, Li S, Chen P, Wang L, Yu H, et al. Curcumin alleviates palmitic acid-induced LOX-1 upregulation by suppressing endoplasmic reticulum stress in HUVECs. Biomed Res Int 2021; 2021: 9983725.
40. Zingg JM, Hasan ST, Cowan D, Ricciarelli R, Azzi A, Meydani M. Regulatory effects of curcumin on lipid accumulation in monocytes/macrophages. J Cell Biochem 2012; 113: 833-840.
41. Shin SK, Ha TY, McGregor RA, Choi MS. Long-term curcumin administration protects against atherosclerosis via hepatic regulation of lipoprotein cholesterol metabolism. Mol Nutr Food Res 2011; 55: 1829-1840.
42. Mizushima N, Ohsumi Y, Yoshimori T. Autophagosome formation inmammalian cells. Cell Struct Funct 2002; 27: 421‐429.
43. Zhu W, Yuan Y, Liao G, Li L, Liu J, Chen Y, et al. Mesenchymal stem cells ameliorate hyperglycemia-induced endothelial injury through modulation of mitophagy. Cell Death Dis 2018; 9: 837-853.
44. Liao X, Sluimer JC, Wang Y, Subramanian M, Brown K, Pattison JS, et al. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab 2012; 15: 545-553.
45. Razani B, Feng C, Coleman T, Emanuel R, Wen H, Hwang S, et al. Autophagy links inflammasomes to atherosclerotic progression. Cell Metab 2012; 15: 534-544.
46. Choi SE, Lee SM, Lee YJ, Li LJ, Lee SJ, Lee JH, et al. Protective role of autophagy in palmitate-induced INS-1 beta-cell death. Endocrinology 2009; 150:126-134.
47. Wu H, Wang MC, Bohmann D. JNK protects Drosophila from oxidative stress by trancriptionally activating autophagy. Mech Dev 2009; 126: 624-637.
48. Han J, Pan XY, Xu Y, Xiao Y, An Y, Tie L, et al. Curcumin induces autophagy to protect vascular endothelial cell survival from oxidative stress damage. Autophagy 2012; 8: 812-825.
49. Wang G, Zhu Y, Li K, Liao B, Wang F, Shao L, et al. Curcumin-mediated photodynamic therapy inhibits the phenotypic transformation, migration, and foaming of oxidized low-density lipoprotein-treated vascular smooth muscle cells by promoting autophagy. J Cardiovasc Pharmacol 2021; 78: 308-318.
50.Inoki K, Kim J, Guan KL. AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharmacol Toxicol 2012; 52: 381-400.
51.Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13: 132-141.
52.Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature 2008; 451: 1069-1075.
53.Chen WR, Yang JQ, Liu F, Shen XQ, Zhou YJ. Melatonin attenuates vascular calcification by activating autophagy via an AMPK/mTOR/ULK1 signaling pathway. Exp Cell Res 2020; 389: 111883.
54.Li Y, Chen C, Yao F, Su Q, Liu D, Xue R, et al. AMPK inhibits cardiac hypertrophy by promoting autophagy via mTORC1. Arch Biochem Biophys 2014; 558: 79-86.
55. Guo S, Long M, Li X, Zhu S, Zhang M, Yang Z. Curcumin activates autophagy and attenuates oxidative damage in EA.hy926 cells via the Akt/mTOR pathway. Mol Med Rep 2016  13: 2187-2193.
the primers used are listed in the supplementary material (Supplementary Table S1).
References
1.Endemann DH, Schiffrin EL. Endothelial dysfunction. J Am Soc Nephrol 2004; 15: 1983-1992.
2.Bernhard D, Wang XL. Smoking, oxidative stress and cardiovascular diseases-do anti-oxidative therapies fail? Curr Med Chem 2007; 14: 1703-1712.
3.Nicolls MR, Haskins K, Flores SC. Oxidant stress, immune dysregulation, and vascular function in type I diabetes. Antioxid Redox Signal 2007; 9: 879‐889.
4.Buday A, Orsy P, Godó M, Mózes M, Kökény G, Lacza Z, et al. Elevated systemic TGF-beta impairs aortic vasomotor function through activation of NADPH oxidase-driven superoxide production and leads to hypertension, myocardial remodeling, and increased plaque formation in apoE(-/-) mice. Am J Physiol Heart Circ Physiol 2010; 299: H386-395.
5.Stary HC. Natural history and histological classification of atherosclerotic lesions:an update. Arterioscler Thromb Vasc Biol 2000; 20: 1177–1178.
6.Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20: 1262–1275.
7.Simionescu N, Vasile E, Lupu F, Popescu G, Simionescu M. Prelesional events in atherogenesis. Accumulation of extracellular cholesterol-rich liposomes in the arterial intima and cardiac valves of the hyperlipidemic rabbit. The American journal of pathology 1986; 123: 109–125.
8.Ross R, Glomset JA. Atherosclerosis and the arterial smooth muscle cell: Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science 1973; 180: 1332–1339.
9.Ross R, Glomset JA. The pathogenesis of atherosclerosis (first of two parts). N Engl J Med 1976; 295: 369–377.
10.Zhang X, Han X, Zhang P, Zhou T, Chen Y, Jin J, et al. Morin attenuates oxidized low-density lipoprotein-mediated injury by inducing autophagy via activating AMPK signalling in HUVECs. Clin Exp Pharmacol Physiol 2019; 46: 1053-1060.
11.Luo RX, Li LZ, Liu XH, Yuan YJ, Zhu WZ, Li L, et al. Mesenchymal stem cells alleviate palmitic acid-induced endothelial-to-mesenchymal transition by suppressing endoplasmic reticulum stress. Am J Physiol Endocrinol Metab 2010; 319: E961-980.
12.Yamagata K, Yamori Y. Inhibition of endothelial dysfunction by dietary flavonoids and preventive effects against cardiovascular disease. J Cardiovasc Pharmacol 2020; 75: 1-9.
13.Tomonori A, Daisuke S, Noriaki T, Seiji T, Eiichiro Y, Yasuhiro I, et al. Effects of the mean amplitude of glycemic excursions and vascular endothelial dysfunction on cardiovascular events in nondiabetic patients with coronary artery disease. J Am Heart Assoc 2017; 6: e004841.
14.Yang Z, Klionsky DJ. Eaten alive: a history of macroautophagy. Nat Cell Biol 2010; 12: 814‐822.
15. Puleston DJ, Simon AK. Autophagy in the immune system. Immunology 2014; 141: 1‐8.
16.Ouimet M. Autophagy in obesity and atherosclerosis: interrelationships between cholesterol homeostasis, lipoprotein metabolism and autophagy in macrophages and other systems. Biochim Biophys Acta 2013; 183: 1124‐1133.
17.Muller C, Salvayre R, Negre‐Salvayre A, Vindis C. Oxidized LDLs trigger endoplasmic reticulum stress and autophagy: prevention by HDLs. Autophagy 2011; 7: 541‐543.
18.Perrotta I, Aquila S. The Role of Oxidative Stress and Autophagy in Atherosclerosis. Oxid Med Cell Longev 2015; 2015: 130315.
19.Le Guezennec X, Brichkina A, Huang YF, Kostromina E, Han W, Bulavin DV. Wip1-dependent regulation of autophagy, obesity, and atherosclerosis. Cell Metab 2012; 16: 68-80.
20.Shan R, Liu N, Yan Y, Liu B. Apoptosis, autophagy and atherosclerosis: relationships and the role of Hsp27. Pharmacol Res 2020; 11: 105169.
21.Peng S, Xu LW, Che XY, Xiao QQ, Pu J, Shao Q, et al. Atorvastatin inhibits inflammatory response, attenuates lipid deposition, and improves the stability of vulnerable atherosclerotic plaques by modulating autophagy. Front Pharmacol 2018; 9: 438.
22.Zhang N, Zhi XY, Zhao J, Wei JL, Li JP, Yang HF. Mesoporous silica induces hippocampal neurons cell autophagy through AMPK/mTOR/P70S6K signaling pathway. Environ Toxicol 2020; 35: 176-187.
23.Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13: 132‐141.
24.Zhang P, Liu X, Li H, Chen Z, Yao X, Jin J, et al. TRPC5‐induced autophagy promotes drug resistance in breast carcinoma via CaMKKbeta/AMPKalpha/mTOR pathway. Sci Rep 2017; 7: 3158.
25.Kim Y C, Guan K L. mTOR: a pharmacologic target for autophagy regulation. J Clin Invest 2015; 125: 25-32.
26.Sun XW, Wang DY, Zhang TT, Lu XJ, Duan FF, Ju LI, et al. Eugenol attenuates cerebral ischemia-reperfusion injury by enhancing autophagy via AMPK-mTOR-P70S6K pathway. Front Pharmacol 2020; 11: 84.
27.Wang P, Jiang LZ, Zhou N, Zhou H, Liu HZ, Zhao WR, et al. Resveratrol ameliorates autophagic flux to promote functional recovery in rats after spinal cord injury. Oncotarget 2018; 9: 8427-8440.
28.Mohammadian HS, Karimzadeh MR, Azhdari S, Vahedi P, Abdollahi E, Momtazi-Borojeni AA. Modulatory effects of curcumin on the atherogenic activities of inflammatory monocytes: Evidence from in vitro and animal models of human atherosclerosis. Biofactors 2020; 46: 341-355
29.Zhou YY, Zhang TT, Wang XF, Wei XW, Chen YZ, Guo LY, et al. Curcumin modulates macrophage polarization through the inhibition of the Toll-like receptor 4 expression and its signaling pathways. Cell Physiol Biochem 2015; 36: 631-641.
30.Batra H, Pawar S, Bahl D. Curcumin in combination with anti-cancer drugs: A nanomedicine review. Pharmacol Res 2019; 139: 91-105.
31.Zhang S, Zou J, Li P, Zheng X, Feng D. Curcumin protects against atherosclerosis in apolipoprotein E-Knockout mice by inhibiting Toll-like receptor 4 expression. J Agric Food Chem 2018; 66: 449-456.
32.Zou J, Zhang S, Li P, Zheng X, Feng D. Supplementation with curcumin inhibits intestinal cholesterol absorption and prevents atherosclerosis in high-fat diet-fed apolipoprotein E knockout mice. Nutr Res 2018; 56: 32-40.
33.Shakeri A, Cicero AFG, Panahi Y, Mohajeri M, Sahebkar A. Curcumin: A naturally occurring autophagy modulator. J Cell Physiol 2019; 234: 5643-5654.
34.Carmeliet P. Angiogenesis in life, disease and medicine. Nature 2005; 438: 932-936.
35.Yamagata K. Docosahexaenoic acid regulates vascular endothelial cell function and prevents cardiovascular disease. Lipids Health Dis 2017; 16: 118.
36.Wang Z, Wang Y, Chen Y, Lv J. The IL-24 gene protects human umbilical vein endothelial cells against H₂O₂-induced injury and may be useful as a treatment for cardiovascular disease. Int J Mol Med 2016; 37: 581-592.
37.Guo N, Chen F, Zhou J, Fang Y, Li H, Luo Y, et al. Curcumin attenuates rapamycin-induced cell injury of vascular endothelial cells. J Cardiovasc Pharmacol 2015; 66: 338-346.
38.Li J, Luo M, Xie N, Wang J, Chen L. Curcumin protects endothelial cells against homocysteine induced injury through inhibiting inflammation. Am J Transl Res 2016; 8: 4598-4604.
39. Luo R, Zhao L, Li S, Chen P, Wang L, Yu H, et al. Curcumin Alleviates Palmitic Acid-Induced LOX-1 Upregulation by Suppressing Endoplasmic Reticulum Stress in HUVECs. Biomed Res Int 2021 Aug 22; 2021: 9983725.
40.Zingg JM, Hasan ST, Cowan D, Ricciarelli R, Azzi A, Meydani M. Regulatory effects of curcumin on lipid accumulation in monocytes/macrophages. J Cell Biochem 2012; 113: 833-840.
41.Shin SK, Ha TY, McGregor RA, Choi MS. Long-term curcumin administration protects against atherosclerosis via hepatic regulation of lipoprotein cholesterol metabolism. Mol Nutr Food Res 2011; 55: 1829-1840.
42.Mizushima N, Ohsumi Y, Yoshimori T. Autophagosome formation inmammalian cells. Cell Struct Funct 2002; 27: 421‐429.
43.Zhu W, Yuan Y, Liao G, Li L, Liu J, Chen Y, et al. Mesenchymal stem cells ameliorate hyperglycemia-induced endothelial injury through modulation of mitophagy. Cell Death Dis 2018; 9: 837.
44.Liao X, Sluimer JC, Wang Y, Subramanian M, Brown K, Pattison JS, et al. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab 2012; 15: 545-553.
45.Razani B, Feng C, Coleman T, Emanuel R, Wen H, Hwang S, et al. Autophagy links inflammasomes to atherosclerotic progression. Cell Metab 2012; 15: 534-544.
46. Choi SE, Lee SM, Lee YJ, Li LJ, Lee SJ, Lee JH, et al. Protective role of autophagy in palmitate-induced INS-1 beta-cell death. Endocrinology 2009 Jan; 150(1):126-134.
47.Wu H, Wang MC, Bohmann D. JNK protects Drosophila from oxidative stress by trancriptionally activating autophagy. Mech Dev 2009 Aug-Sep; 126(8-9): 624-637.
48.Han J, Pan XY, Xu Y, Xiao Y, An Y, Tie L, et al. Curcumin induces autophagy to protect vascular endothelial cell survival from oxidative stress damage. Autophagy 2012 May 1; 8(5): 812-825.
49.Wang G, Zhu Y, Li K, Liao B, Wang F, Shao L, et al. Curcumin-mediated Photodynamic Therapy Inhibits the Phenotypic Transformation, Migration, and Foaming of Oxidized Low-density Lipoprotein-treated Vascular Smooth Muscle Cells by Promoting Autophagy. J Cardiovasc Pharmacol 2021 Jun 2; 78(2): 308-318.
50.Inoki K, Kim J, Guan KL. AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharmacol Toxicol 2012; 52: 381-400.
51.Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13: 132-141.
52.Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature 2008; 451: 1069-1075.
53.Chen WR, Yang JQ, Liu F, Shen XQ, Zhou YJ. Melatonin attenuates vascular calcification by activating autophagy via an AMPK/mTOR/ULK1 signaling pathway. Exp Cell Res 2020; 389: 111883.
54.Li Y, Chen C, Yao F, Su Q, Liu D, Xue R, et al. AMPK inhibits cardiac hypertrophy by promoting autophagy via mTORC1. Arch Biochem Biophys 2014; 558: 79-86.
55. Guo S, Long M, Li X, Zhu S, Zhang M, Yang Z. Curcumin activates autophagy and attenuates oxidative damage in EA.hy926 cells via the Akt/mTOR pathway. Mol Med Rep 2016 Mar; 13(3): 2187-2193.
Iranian Journal of Basic Medical Sciences
Volume 24, Issue 12
December 2021
Pages 1734-1742

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