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The role of endoplasmic reticulum stress and NLRP3-inflammasomes in the development of atherosclerosis

Pushkarev V.V., Sokolova L.K., Kovzun O.I., Pushkarev V.M., Tronko M.D.

Review 

SUMMARY. Endoplasmic reticulum (ER) plays a central role in the synthesis of proteins and their post-translational modification by folding newly synthesized proteins through the formation of disulfide bonds, which is necessary to achieve their final stable conformational state. ER homeostasis is stressed when the influx of newly synthesized unfolded or misfolded polypeptide chains exceeds the ER capacity for repair and refolding. ER stress in diabetes can be caused by various factors that inhibit protein folding, such as glucose, non-esterified cholesterol, oxidized phospholipids, saturated fatty acids, and ROS. Chronic ER stress leads to the death of pancreatic β-cells, increases hyperglycemia, and is the main etiology of diabetes. Atherosclerosis (AS) is a chronic inflammatory disease that is the basis of the pathology of ischemic cardiovascular and cerebrovascular diseases. It has been documented that both endoplasmic reticulum (ER) stress and NLRP3-inflammasomes influence the progression of AS. The ER stress response in endothelial cells leads to inflammation and cell death in diabetes-related vascular diseases. ER stress also plays a key role in the onset of atherosclerosis in diabetes, which is a major consequence of endothelial dysfunction. Several independent risk factors for cardiovascular diseases, in addition to hyperglycemia – hyperhomocysteinemia, obesity, and dyslipidemia are
also associated with ER stress, which indicates its integrating function in atherogenesis. The etiological role of low-level tissue inflammation in the formation of insulin resistance and β-cell dysfunction in type 2 diabetes is generally recognized. Among innate immune receptors, NLRP3 plays a critical role in tissue inflammation associated with lipid overload or obesity. The research has shown that ER stress is involved in inflammation and plays a key role for the ER in the activation of NLRP3-inflammasomes, which trigger the secretion of pro-inflammatory cytokines such as IL-1β and IL-18. Metformin, an AMPK activator, inhibits ER stress and restores endothelial cell function in diabetes. Metformin inhibits NLRP3-inflammasome activation under ER stress through suppression of IL-6 and MCP-1 production induced by high glucose levels, decrease in TXNIP expression, and activation of autophagy via AMPK.

Key words: diabetes, atherosclerosis, endoplasmic reticulum stress, NLRP3-inflammasomes, metformin

Tsitologiya i Genetika 2021, vol. 55, no. 4, pp. 43-53

• SI «V.P. Komisarenko Institute of endocrinology and metabolism of NAMS of Ukraine», Kyiv

E-mail: pushkarev.vm gmail.com

Pushkarev V.V., Sokolova L.K., Kovzun O.I., Pushkarev V.M., Tronko M.D. The role of endoplasmic reticulum stress and NLRP3-inflammasomes in the development of atherosclerosis, Tsitol Genet., 2021, vol. 55, no. 4, pp. 43-53.

In "Cytology and Genetics":
The Role of Endoplasmic Reticulum Stress and NLRP3 Inflammasomes in the Development of Atherosclerosis V. V. Pushkarev, L. K. Sokolova, O. I. Kovzun, V. M. Pushkarev & M. D. Tronko, Cytol Genet., 2021, vol. 55, no. 4, pp. 331–339
DOI: 10.3103/S0095452721040113

References

1. Agouni, A., Tual-Chalot, S., Chalopin, M., et al., Hepatic protein tyrosine phosphatase 1B (PTP1B) deficiency protects against obesity-induced endothelial dysfunction, Biochem. Pharmacol., 2014, vol. 92, pp. 607–617. https://doi.org/10.1016/j.bcp.2014.10.008

2. Bronner, D.N., Abuaita, B.H., Chen, X., et al., Endoplasmic reticulum stress activates the inflammasome via NLRP3- and caspase-2-driven mitochondrial damage, Immunity, 2015, vol 43, pp. 451–462. https://doi.org/10.1016/j.immuni.2015.08.008

3. Chai, T.F., Hong, S.Y., He, H., et al., A potential mechanism of metformin-mediated regulation of glucose homeostasis: inhibition of thioredoxin-interacting protein (TXNIP) gene expression, Cell Signal., 2012, vol. 24, pp. 1700–1705.https://doi.org/10.1016/j.cellsig.2012.04.017

4. Cheang, W.S., Tian, X.Y., Wong, W.T., et al., Metformin protects endothelial function in diet-induced obese mice by inhibition of endoplasmic reticulum stress through 5' adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor delta pathway, Arterioscler. Thromb. Vase Biol., 2014, vol. 34, no. 4, pp. 830–836. https://doi.org/10.1161/ATVBAHA.113.301938

5. Chen, X., Guo, X., Ge, Q., et al., ER stress activates the NLRP3 inflammasome: a novel mechanism of atherosclerosis, Oxid. Med. Cell Longev., 2019a, p. 3462530. https://doi.org/10.1155/2019/3462530

6. Chen, C., Kassan, A., Castaceda, D., et al., Metformin prevents vascular damage in hypertension through the AMPK/ER stress pathway, Hypertens. Res., 2019b, vol. 42, no. 7, pp. 960–969. https://doi.org/10.1038/s41440-019-0212-z

7. Chen, Y., Wang, J.J., Li, J., et al., Activating transcription factor 4 mediates hyperglycaemia-induced endothelial inflammation and retinal vascular leakage through activation of STAT3 in a mouse model of type 1 diabetes, Diabetologia, 2012, vol. 55, no. 9, pp. 2533–2545. https://doi.org/10.1007/sOO125-012-2594-1

8. Cnop, M., Toivonen, S., Igoillo-Esteve, M., and Salpea, P., Endoplasmic reticulum stress and eIF2a phosphorylation: the Achilles heel of pancreatic β cells, Mol. Metab., 2017, vol. 6, no. 9, pp. 1024–1039. https://doi.org/10.1016/j.molmet.2017.06.001

9. Davies, P.F., Civelek, M., Fang, Y., and Fleming, I., The atherosusceptible endothelium: endothelial phenotypes in complex haemodynamic shear stress regions in vivo, Cardiovasc. Res., 2013, vol. 99, no. 2, pp. 315–327. https://doi.org/10.1093/cvr/cvtl01

10. de la Roche, M., Hamilton, C., Mortensen, R., et al., Trafficking of cholesterol to the ER is required for NLRP3 inflammasome activation, J. Cell Biol., 2018, vol. 217, pp. 3560–3576. https://doi.org/10.1083/jcb.201709057

11. Dong, Y., Zhang, M., Wang, S., et al., Activation of AMP-activated protein kinase inhibits oxidized LDL-triggered endoplasmic reticulum stress in vivo, Diabetes, 2010, vol. 59, no. 6, pp. 1386–1396. https://doi.org/10.2337/db09-1637

12. Flamment, M., Hajduch, E., Ferre, P., and Foufelle, F., New insights into ER stress-induced insulin resistance, Trends Endocrinol. Metab., 2012, vol. 23, pp. 381–390.https://doi.org/10.1016/j.tem.2012.06.003

13. Fonseca, S.G., Gromada, J., and Urano, F., Endoplasmic reticulum stress and pancreatic beta-cell death, Trends Endocrinol. Metab., 2011, vol. 22, no. 7, pp. 266–274.https://doi.org/10.1016/j.tem.2011.02.008

14. Galan, M., Kassan, M., Choi, S.K., et al., A novel role for epidermal growth factor receptor tyrosine kinase and its downstream endoplasmic reticulum stress in cardiac damage and microvascular dysfunction in type 1 diabetes mellitus, Hypertension, 2012, vol. 60, pp. 71–80. https://doi.org/10.1161/HYPERTENSIONAHA.11.192500

15. Galan, M., Kassan, M., Kadowitz, P.J., et al., Mechanism of endoplasmic reticulum stress-induced vascular endothelial dysfunction, Biochim. Biophys. Acta, 2014, vol.1843, pp. 1063–1075.https://doi.org/10.1016/j.bbamcr.2014.02.009

16. Gardner, B.M., Pincus, D., Gotthardt, K., et al., Endoplasmic reticulum stress sensing in the unfolded protein response, Cold Spring Harb. Perspect. Biol., 2013, vol. 5, art. a013169. https://doi.org/10.1101/cshperspect.a013169

17. Ghemrawi, R., Battaglia-Hsu, S.F., and Arnold, C., Endoplasmic reticulum stress in metabolic disorders, Cells, 2018, vol. 7, no. 6, p. 63. https://doi.org/10.3390/cells7060063

18. He, Y., Hara, H., and Nunez, G., Mechanism and regulation of NLRP3 inflammasome activation, Trends Biochem. Sci., 2016, vol. 41, pp. 1012–1021. doi . 09.002https://doi.org/10.1016/j.tibs.2016

19. Hossain, G.S., Lynn, E.G., Maclean, K.N., et al., Deficiency of TDAG51 protects against atheroclerosis by modulating apoptosis, cholesterol efflux, and peroxiredoxin-1 expression, J. Am. Heart Assoc., 2013, vol. 2, no. 3, e000134. https://doi.org/10.1161/JAHA.113.000134

20. Hu, M., Phan, F., Bourron, O., et al., Steatosis and NASH in type 2 diabetes, Biochimie, 2017, vol. 143, pp. 37–41. https://doi.org/10.1016/j.biochi.2017.10.019

21. Hur, K.Y. and Lee, M.S., New mechanisms of metformin action: focusing on mitochondria and the gut, J. Diabetes Invest., 2015, vol. 6, no. 6, pp. 600–609. https://doi.org/10.1111/jdi.12328

22. Inagi, R., Ishimoto, Y., and Nangaku, M., Proteostasis in endoplasmic reticulum—new mechanisms in kidney disease, Nat. Rev. Nephrol., 2014, vol. 10, no. 7, pp. 369–378. https://doi.org/10.1038/nrneph.2014.67

23. Incalza, M.A., D’Oria, R., Natalicchio, A., et al., Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases, Vasc. Pharmacol., 2018, vol. 100, pp. 1–19. https://doi.org/10.1016/j.vph.2017.05.005

24. Jamwal, S. and Sharma, S., Vascular endothelium dysfunction: a conservative target in metabolic disorders, Inflamm. Res., 2018, vol. 67, pp. 391–405. https://doi.org/10.1007/s00011-018-1129-8

25. Kim, S., Joe, Y., Jeong, S.O., et al., Endoplasmic reticulum stress is sufficient for the induction of IL-1 beta production via activation of the NF-kappa B and inflammasome pathways, Innate Immun., 2014, vol. 20, pp. 799–815. https://doi.org/10.1177/1753425913508593

26. Kornfeld, O.S., Hwang, S., Disatnik, M.H., et al., Mitochondrial reactive oxygen species at the heart of the matter: new therapeutic approaches for cardiovascular diseases, Circ. Res., 2015, vol. 116, pp. 1783–1799. https://doi.org/10.1161/CIRCRESAHA.116.305432

27. Lebeaupin, C., Proics, E., de Bieville, C.H., et al., ER stress induces NLRP3 inflammasome activation and hepatocyte death, Cell Death Dis., 2015, vol. 6, e1879. https://doi.org/10.1038/cddis.2015.248

28. Lee, H.M., Kim, J.J., Kim, H.J., et al., Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes, Diabetes, 2013, vol. 62, pp. 194–204. https://doi.org/10.2337/db12-0420

29. Lenna, S., Han, R., and Trojanowska, M., Endoplasmic reticulum stress and endothelial dysfunction, IUBMB Life, 2014, vol. 66, no. 8, pp. 530–537. https://doi.org/10.1002/iub.1292

30. Lerner, A.G., Upton, J.P., Praveen, P.V., et al., IRE1 a induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress, Cell Metab., 2012, vol. 16, pp. 250–264. https://doi.org/10.1016/j.cmet.2012.07.007

31. Li, A., Zhang, S., Li, J., et al., Metformin and resveratrol inhibit drp1-mediated mitochondrial fission and prevent ER stress-associated NLRP3 inflammasome activation in the adipose tissue of diabetic mice, Mol. Cell Endocrinol., 2016, vol. 434, pp. 36–47. https://doi.org/10.1016/j.mce.2016.06.008

32. Liang, B., Wang, S., Wang, Q., et al., Aberrant endoplasmic reticulum stress in vascular smooth muscle increases vascular contractility and blood pressure in mice deficient of AMP-activated protein kinase-α 2 in vivo, Arterioscler. Thromb. Vasc. Biol., 2013, vol. 33, pp. 595–604. https://doi.org/10.1161/ATVBAHA.112.300606

33. Lisa, S., Domingo, B., Martinez, J., et al., Failure of prion protein oxidative folding guides the formation of toxic transmembrane forms, J. Biol. Chem., 2012, vol. 287, pp. 36693–36701. https://doi.org/10.1074/jbc.M112.398776

34. Liu, Q., Zhang, D., Hu, D., et al., The role of mitochondria in NLRP3 infiammasome activation, Mol. Immunol., 2018, vol. 103, pp. 115–124. https://doi.org/10.1016/j.molimm.2018.09.010

35. Lytrivi, M., Castell, A.L., Poitout, V., and Cnop, M., Recent insights into mechanisms of β-cell lipo- and glucolipotoxicity in type 2 diabetes, J. Mol. Biol., 2020, vol. 432, no. 5, pp. 1514–1534. https://doi.org/10.1016/j.jmb.2019.09.016

36. Maamoun, H., Zachariah, M., McVey, J.H., et al., Heme oxygenase (HO)-1 induction prevents endoplasmic reticulum stress-mediated endothelial cell death and impaired angiogenic capacity, Biochem. Pharmacol., 2017, vol. 127, pp. 46–59. https://doi.org/10.1016/j.bcp.2016.12.009

37. Maamoun, H., Abdelsalam, S.S., Zeidan, A., et al., Endoplasmic reticulum stress: a critical molecular driver of endothelial dysfunction and cardiovascular disturbances associated with diabetes, Int. J. Mol. Sci., 2019a, vol. 20, no. 7, p. 1658. https://doi.org/10.3390/ijms20071658

38. Maamoun, H., Benameur, T., Pintus, G., et al., Crosstalk between oxidative stress and endoplasmic reticulum (ER) stress in endothelial dysfunction and aberrant angiogenesis associated with diabetes: a focus on the protective roles of heme oxygenase (HO)-1, Front. Physiol., 2019b, vol. 10, p. 70. https://doi.org/10.3389/fphys.2019.00070

39. Misawa, T., Takahama, M., Kozaki, T., et al., Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome, Nat. Immunol., 2013, vol. 14, pp. 454–460. https://doi.org/10.1038/ni.2550

40. Mohan, S., Rani, P.R.M., Brown, L., et al., Endoplasmic reticulum stress: a master regulator of metabolic syndrome, Eur. J. Pharmacol., 2019, vol. 860, p. 172553. https://doi.org/10.1016/j.ejphar.2019.172553

41. Muller, C., Salvayre, R., Negre-Salvayre, A., and Vindis, C., HDLs inhibit endoplasmic reticulum stress and autophagic response induced by oxidized LDLs, Cell Death Differ., 2011, vol. 18, no. 5, pp. 817–828. https://doi.org/10.1038/cdd.2010.149

42. Oslowski, C.M., Hara, T., O’Sullivan-Murphy, B., et al., Thioredoxin-interacting protein mediates ER stress-induced B cell death through initiation of the inflammasome, Cell Metab., 2012, vol. 16, pp. 265–273. https://doi.org/10.1016/j.cmet.2012.07.005

43. Owen, C., Lees, E.K., Grant, L., et al., Inducible liver-specific knockdown of protein tyrosine phosphatase 1B improves glucose and lipid homeostasis in adult mice, Diabetologia, 2013, vol. 56, pp. 2286–2296. https://doi.org/10.1007/s00125-013-2992-z

44. Ozcan, L. and Tabas, I., Role of endoplasmic reticulum stress in metabolic disease and other disorders, Ann. Rev. Med., 2012, vol. 63, pp. 317–328.

45. Pushkarev, V.M., Sokolova, L.K., Pushkarev, V.V., and Tronko, M.D., The role of AMPK and mTOR in the development of insulin resistance and type 2 diabetes. The mechanism of metformin action, Probl. Endocrin. Pathol., 2016, vol. 3, pp. 77–90.

46. Shi, C.S., Shenderov, K., Huang, N.N., et al., Activation of autophagy by inflammatory signals limits IL-1b production by targeting ubiquitinated inflammasomes for destruction, Nat. Immunol., 2012, vol. 13, pp. 255–263. https://doi.org/10.1038/ni.2215

47. Sokolova, L.K., Pushkarev, V.M., Belchina, Y.B., et al., Effect of combined treatment with insulin and metformin on 5'AMP-activated protein kinase activity in lymphocytes of diabetic patients, Dopov. Nac. Akad. Nauk Ukr., 2018, vol. 5, pp. 100–104. https://doi.org/10.15407/dopovidi2018.05.100

48. Sokolova, L.K., Pushkarev, V.M., Pushkarev, V.V., et al., Diabetes mellitus and atherosclerosis. The role of inflammatory processes in pathogenesis, Mezhdunarod. Endokrinol. Zh., 2017, vol. 13, no. 7, pp. 486–498.

49. Son, S.M. Reactive oxygen and nitrogen species in pathogenesis of vascular complications of diabetes, Diabetes Metab. J., 2012, vol. 36, pp. 190–198. https://doi.org/10.4093/dmj.2012.36.3.190

50. Tabas, I., The role of endoplasmic reticulum stress in the progression of atherosclerosis, Circ. Res., 2010, vol. 107, no. 7, pp. 839–850. doi . 224766https://doi.org/10.1161/CIRCRESAHA.110

51. Talty, A., Deegan, S., Ljujic, M., et al., Inhibition of IRE1alpha RNase activity reduces NLRP3 inflammasome assembly and processing of pro-IL1beta, Cell Death Dis., 2019, vol. 10, p. 622. https://doi.org/10.1038/s41419-019-1847-z

52. Thon, M., Hosoi, T., Yoshii, M., and Ozawa, K., Leptin induced GRP78 expression through the PI3K-mTOR pathway in neuronal cells, Sci. Rep., 2014, vol. 4, p. 7096. https://doi.org/10.1038/srep07096

53. Tronko, N.D., Pushkarev, V.M., Sokolova, L.K., et al., Molecular Mechanisms of Pathogenesis of Diabetes and Its Complications, Kyiv: Medkniga, 2018.

54. Tufanli, O., Telkoparan Akillilar, P., Acosta-Alvear, D., et al., Targeting IRE1 with small molecules counteracts progression of atherosclerosis, Proc. Natl. Acad. Sci. U. S. A., 2017, vol. 114, pp. E1395–E1404. https://doi.org/10.1073/pnas.1621188114

55. Vandanmagsar, B., Youm, Y.H., Ravussin, A., et al., The NLRP3 inflammasome instigate obesity-induced inflammation and insulin resistance, Nat. Med., 2011, vol. 15, pp. 179–188. https://doi.org/10.1038/nm.2279

56. Walter, P. and Ron, D., The unfolded protein response: from stress pathway to homeostatic regulation, Science, 2011, vol. 334, pp. 1081–1086. https://doi.org/10.1126/science.1209038

57. Wang, Y.I., Bettaieb, A., Sun, C., et al., Triglyceride-rich lipoprotein modulates endothelial vascular cell adhesion molecule (VCAM)-1 expression via differential regulation of endoplasmic reticulum stress, PLoS One, 2013, vol. 8, no. 10, e78322. https://doi.org/10.1371/journal.pone.0078322

58. Ye, J., Mechanisms of insulin resistance in obesity, Front. Med., 2013, vol. 7, no. 1, pp. 14–24. https://doi.org/10.1007/s11684-013-0262-6

59. Zhou, J., Massey, S., Story, D., and Li, L., Metformin: an old drug with new applications, Int. J. Mol. Sci., 2018, vol. 19, no. 10, p. 2863. https://doi.org/10.3390/ijms19102863

60. Zhou, R., Tardivel, A., Thorens, B., et al., Thioredoxin-interacting protein links oxidative stress to inflammasome activation, Nat. Immunol., 2010, vol 11, pp. 136–140. https://doi.org/10.1038/ni.1831

61. Zhou, Y., Tong, Z., Jiang, S., et al., The roles of endoplasmic reticulum in NLRP3 inflammasome activation, Cell, 2020, vol. 9, no. 5, p. 1219. https://doi.org/10.3390/cells9051219

62. Zoungas, S., Chalmers, J., Ninomiya, T., et al., Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: evidence of glycaemic thresholds, Diabetologia, 2012, vol. 55, no. 3, pp. 636–643. https://doi.org/10.1007/s00125-011-2404-1