Small Chain Fatty Acid Phenylbutyric Acid Alleviated Inflammation-Induced Endoplasmic Reticulum Stress in Endothelial Cells
Abstract
Endothelial cells (EC) have dynamic properties and high plasticity in response to microenvironmental change. A proinflammatory cytokine such as tumor necrotizing factor-α (TNF-α) can induce EC phenotype shift to osteoinduction properties by releasing a potent osteogenic cytokine, namely bone morphogenetic protein 2 (BMP2). Normally BMP2 acts as an osteoblast stimulating factor in bone and cartilage tissue. BMP2 activation in vascular tissue will invite osteoblast recruitment and mineralization and generated pathological vascular stiffening and calcification. Recently, endoplasmic reticulum stress (ERS) has been emerging as a new target therapy in many vascular diseases such as vascular stiffening and calcification. Some short-chain fatty acid like 4-phenyl butyric acid has been shown had anti-ERS properties. However, the role of 4-phenyl butyric acid in BMP2 inhibition in endothelial cells is still poorly understood. Hence, we investigated the role of 4-phenyl butyric acid in inflammation-induced BMP2 expression in human vein derived endothelial cells. Endothelial cells obtained from a baby born umbilical vein were cultured and pre-treated with TNF-α (5 ng/ml) as inflammation precondition. Multiple doses of 4-phenyl butyrate acid (4-PBA) 1 nM/mL, 2 nM/mL, and 3 nM/m were used as ERS inhibitors. The expression of two ERS biomarkers, glucose-related protein-8 (GRP78) and activating transcription factor-6 (ATF6), were measured. Statistical analysis was done using one-way ANOVA and Kruskal Wallis tests, and P<0.01 considered as significant. 4-PBA decrease luminal BMP2 at dose one nM/L, GRP78 at dose 1 nM/L, and translocated ATF6 expression at dose 1 nM/L in endothelial culture dose-dependently. Short-chain fatty acid 4-phenylbutyrate acid decreases luminal ERS marker GRP78 and translocated ATF6 expression in endothelial culture. ERS has a role in osteoinductive phenotype shifting in inflammation endothelial cells, which was the novelty of this research. Further research needs to elucidate ERS inhibition in in vivo experiment
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2. Ballermann BJ. Endothelial Cell Identity, Heterogeneity and Plasticity in the Kidney. J Am Soc Nephrol 2020;31:1-2.
3. Keshavarz S, Nassiri SM, Siavashi V, Alimi NS. Regulation of plasticity and biological features of endothelial progenitor cells by MSC-derived SDF-1. Biochim Biophys Acta Mol Cell Res 2019;1866:296-304.
4. Krenning G, Barauna VG, Krieger JE, Harmsen MC, Moonen JR. Endothelial Plasticity: Shifting Phenotypes through Force Feedback. Stem Cells Int 2016;2016:9762959.
5. Pikilidou MI, Yavropoulou MP, Scuteri A. Can antihypertensive medication interfere with the vicious cycle between hypertension and vascular calcification? Cardiovasc Drugs Ther 2014;28:61-71.
6. AlGhatrif M, Lakatta EG. The conundrum of arterial stiffness, elevated blood pressure, and aging. Curr Hypertens Rep 2015;17:12.
7. Lyle AN, Raaz U. Killing Me Unsoftly: Causes and Mechanisms of Arterial Stiffness. Arterioscler Thromb Vasc Biol 2017;37:e1-11.
8. Rocha-Singh KJ, Zeller T, Jaff MR. Peripheral arterial calcification: prevalence, mechanism, detection, and clinical implications. Catheter Cardiovasc Interv 2014;83:E212-20.
9. Buendia PA, Montes de Oca JA, Madueno A, Merino A, Martin-Malo P, Aljama R, et al. Endothelial microparticles mediate inflammation-induced vascular calcification. FASEB J 2015;29:173-81.
10. Teitelbaum SL. Bone resorption by osteoclasts. Science 2000;289:1504-8.
11. Kitaura HK, Kimura M, Ishida H, Kohara H, Yoshimatsu M, Takano-Yamamoto T. Immunological Reaction in TNF-Alpha-Mediated Osteoclast Formation and Bone Resorption In Vitro and In Vivo. Clin Dev Immunol 2013;2013:181849.
12. Shao JS, Cai J, Towler DA. Molecular mechanisms of vascular calcification: lessons learned from the aorta." Arterioscler Thromb Vasc Biol 2006;26:1423-30.
13. Masuda M, Miyazaki-Anzai S, Levi M, Ting TC, Miyazaki M. PERK-eIF2alpha-ATF4-CHOP signaling contributes to TNFalpha-induced vascular calcification. J Am Heart Assoc 2013;2:e000238.
14. Kuragano T, Itoh K, Shimonaka Y, Kida A, Furuta M, Kitamura R, et al . Hepcidin as well as TNF-α are significant predictors of arterial stiffness in patients on maintenance hemodialysis. Nephrol Dial Transplant 2011;26:2663-7.
15. Ramseyer VD, Garvin JL. Tumor necrosis factor-alpha: regulation of renal function and blood pressure. Am J Physiol Renal Physiol 2013;304:F1231-42.
16. Lee HL, Woo KM, Ryoo HM, Baek JH. Tumor necrosis factor-alpha increases alkaline phosphatase expression in vascular smooth muscle cells via MSX2 induction. Biochem Biophys Res Commun 2010;391:1087-92.
17. Hess K, Ushmorov A, Fiedler J, Brenner RE, Wirth T. TNFα promotes osteogenic differentiation of human mesenchymal stem cells by triggering the NF-κB signaling pathway. Bone 2009;45:367-76.
18. Croes M, Oner FC, Kruyt MC, Blokhuis TJ, Bastian O, Dhert WJA, et al. Proinflammatory Mediators Enhance the Osteogenesis of Human Mesenchymal Stem Cells after Lineage Commitment. PLoS ONE 2015;10:e0132781.
19. Lee AS, Kim JS, Lee YJ, Kang DG, Lee HS. Anti-TNF-alpha activity of Portulaca oleracea in vascular endothelial cells. Int J Mol Sci 2012;13:5628-44.
20. Wang XC, Sun WT, Yu CM, Pun SH, Underwood MJ, He GW, et al. ER stress mediates homocysteine-induced endothelial dysfunction: Modulation of IKCa and SKCa channels. Atherosclerosis 2015;242:191-98.
21. Chen GC. Deng C, Li YP. TGF-β and BMP Signaling in Osteoblast Differentiation and Bone Formation. Int J Biol Sci 2012;8:272-88.
22. Nguyen VT, Canciani B, Cirillo F, Anastasia L, Peretti GM, Mangiavini L. Effect of Chemically Induced Hypoxia on Osteogenic and Angiogenic Differentiation of Bone Marrow Mesenchymal Stem Cells and Human Umbilical Vein Endothelial Cells in Direct Coculture. Cells 2020; 9:757.
23. Lambert LM, Pipinos II, Baxter BT, Chatzizisis YS, Ryu SJ, Leighton RI, et al. In vitro measurements of hemodynamic forces and their effects on endothelial cell mechanics at the sub-cellular level. Biomicrofluidics 2018;12:064101.
24. Yin X, Liang Z, Yun Y, Pei L. Intravenous Transplantation of BMP2-Transduced Endothelial Progenitor Cells Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Rats. Cell Physiol Biochem 2015;35:2149-58.
25. da Silva RA, de Camargo Andrade AF, da Silva Feltran G, Fernandes C, de Assis RIF, Ferreira MR, et al. The role of triiodothyronine hormone and mechanically-stressed endothelial cell paracrine signalling synergism in gene reprogramming during hBMSC-stimulated osteogenic phenotype in vitro. Mol Cell Endocrinol 2018;478:151-67.
26. Illiandri, O, Sujuti H, Permatasari N, Soeharto S. Moderate Concentrations of TNF- α Induce BMP-2 Expression in Endothelial Cells. Int J Pharm Clin Res 2016;8:1666-9.
27. Fukui N, Ikeda Y, Ohnuki T, Hikita A, Tanaka S, Yamane S, et al. Proinflammatory Cytokine Tumor Necrosis Factor-α Induces Bone Morphogenetic Protein-2 in Chondrocytes via mRNA Stabilization and Transcriptional Up-regulation. J Biol Chem 2006;281:27229-41.
28. Yamamoto K, Yoshida H, Kokame K, Kaufman RJ, Mori K. Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II. J Biochem 2004;136:343-50.
29. Lee AS. The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods 2005;35:373-81.
30. Zhang HS, Nakajima H, Kato L, Gu T, Yoshitomi K, Nagai H, et al. Selective, potent blockade of the IRE1 and ATF6 pathways by 4-phenylbutyric acid analogues. Br J Pharmacol 2013;170: 822-34.
31. Yao S, Prpic V, Pan F, Wise GE. TNF-alpha upregulates expression of BMP-2 and BMP-3 genes in the rat dental follicle--implications for tooth eruption. Connect Tissue Res 2010;51:59-66.
32. McBride SH, McKenzie JA, Bedrick BS, Kuhlmann P, Pasteris JD, Rosen V, et al. Long bone structure and strength depend on BMP2 from osteoblasts and osteocytes, but not vascular endothelial cells. PLoS One 2014;9:e96862.
33. Beederman M, Lamplot JD, Nan G, Wang J, Liu X, Yin L, et al. BMP signaling in mesenchymal stem cell differentiation and bone formation. J Biomed Sci Eng 2013;6:32-52.
34. Dyer LA, Pi X, Patterson C. The role of BMPs in endothelial cell function and dysfunction. Trends Endocrinol Metab 2014;25:472-80.
35. Majka S, Hagen M, Blackwell T, Harral J, Johnson JA, Gendron R, et al. Physiologic and molecular consequences of endothelial Bmpr2 mutation. Respir Res 2011;12:84.
36. Xiao C, Giacca A, Lewis GF. Sodium phenylbutyrate, a drug with known capacity to reduce endoplasmic reticulum stress, partially alleviates lipid-induced insulin resistance and beta-cell dysfunction in humans. Diabetes 2011;60:918-24.
37. Perlmutter DH. Chemical chaperones: a pharmacological strategy for disorders of protein folding and trafficking. Pediatr Res 2002;52:832-6.
38. Illiandri O. The Role of 4-PBA on TNF-alpha related Apoptosis on Human Vein Endothelial Cells. Bangladesh J Med Sci 2019;18: 391-4.
39. Wu S, Gao X, Yang S, Meng M, Yang X, Ge B. The role of endoplasmic reticulum stress in endothelial dysfunction induced by homocysteine thiolactone. Fundam Clin Pharmacol 2015;29:252-9.
40. Zuo WH, Zeng P, Chen X, Lu YJ, Li A, Wu JB. Promotive effects of bone morphogenetic protein 2 on angiogenesis in hepatocarcinoma via multiple signal pathways. Sci Rep 2016;6:37499.
41. Spitler KM, Matsumoto T, Webb RC. Suppression of endoplasmic reticulum stress improves endothelium-dependent contractile responses in aorta of the spontaneously hypertensive rat. Am J Physiol Heart Circ Physiol 2013;305:H344-53.
42. Spitler KM, Webb RC. CHBPR: Endoplasmic Reticulum Stress Contributes to Aortic Stiffening via pro-Apoptotic and Fibrotic Signaling Mechanisms. Hypertension 2014;63:e40-5.
43. Ivanova EA, Orekhov AN. The Role of Endoplasmic Reticulum Stress and Unfolded Protein Response in Atherosclerosis. Int J Mol Sci 2016;17:193.
2. Ballermann BJ. Endothelial Cell Identity, Heterogeneity and Plasticity in the Kidney. J Am Soc Nephrol 2020;31:1-2.
3. Keshavarz S, Nassiri SM, Siavashi V, Alimi NS. Regulation of plasticity and biological features of endothelial progenitor cells by MSC-derived SDF-1. Biochim Biophys Acta Mol Cell Res 2019;1866:296-304.
4. Krenning G, Barauna VG, Krieger JE, Harmsen MC, Moonen JR. Endothelial Plasticity: Shifting Phenotypes through Force Feedback. Stem Cells Int 2016;2016:9762959.
5. Pikilidou MI, Yavropoulou MP, Scuteri A. Can antihypertensive medication interfere with the vicious cycle between hypertension and vascular calcification? Cardiovasc Drugs Ther 2014;28:61-71.
6. AlGhatrif M, Lakatta EG. The conundrum of arterial stiffness, elevated blood pressure, and aging. Curr Hypertens Rep 2015;17:12.
7. Lyle AN, Raaz U. Killing Me Unsoftly: Causes and Mechanisms of Arterial Stiffness. Arterioscler Thromb Vasc Biol 2017;37:e1-11.
8. Rocha-Singh KJ, Zeller T, Jaff MR. Peripheral arterial calcification: prevalence, mechanism, detection, and clinical implications. Catheter Cardiovasc Interv 2014;83:E212-20.
9. Buendia PA, Montes de Oca JA, Madueno A, Merino A, Martin-Malo P, Aljama R, et al. Endothelial microparticles mediate inflammation-induced vascular calcification. FASEB J 2015;29:173-81.
10. Teitelbaum SL. Bone resorption by osteoclasts. Science 2000;289:1504-8.
11. Kitaura HK, Kimura M, Ishida H, Kohara H, Yoshimatsu M, Takano-Yamamoto T. Immunological Reaction in TNF-Alpha-Mediated Osteoclast Formation and Bone Resorption In Vitro and In Vivo. Clin Dev Immunol 2013;2013:181849.
12. Shao JS, Cai J, Towler DA. Molecular mechanisms of vascular calcification: lessons learned from the aorta." Arterioscler Thromb Vasc Biol 2006;26:1423-30.
13. Masuda M, Miyazaki-Anzai S, Levi M, Ting TC, Miyazaki M. PERK-eIF2alpha-ATF4-CHOP signaling contributes to TNFalpha-induced vascular calcification. J Am Heart Assoc 2013;2:e000238.
14. Kuragano T, Itoh K, Shimonaka Y, Kida A, Furuta M, Kitamura R, et al . Hepcidin as well as TNF-α are significant predictors of arterial stiffness in patients on maintenance hemodialysis. Nephrol Dial Transplant 2011;26:2663-7.
15. Ramseyer VD, Garvin JL. Tumor necrosis factor-alpha: regulation of renal function and blood pressure. Am J Physiol Renal Physiol 2013;304:F1231-42.
16. Lee HL, Woo KM, Ryoo HM, Baek JH. Tumor necrosis factor-alpha increases alkaline phosphatase expression in vascular smooth muscle cells via MSX2 induction. Biochem Biophys Res Commun 2010;391:1087-92.
17. Hess K, Ushmorov A, Fiedler J, Brenner RE, Wirth T. TNFα promotes osteogenic differentiation of human mesenchymal stem cells by triggering the NF-κB signaling pathway. Bone 2009;45:367-76.
18. Croes M, Oner FC, Kruyt MC, Blokhuis TJ, Bastian O, Dhert WJA, et al. Proinflammatory Mediators Enhance the Osteogenesis of Human Mesenchymal Stem Cells after Lineage Commitment. PLoS ONE 2015;10:e0132781.
19. Lee AS, Kim JS, Lee YJ, Kang DG, Lee HS. Anti-TNF-alpha activity of Portulaca oleracea in vascular endothelial cells. Int J Mol Sci 2012;13:5628-44.
20. Wang XC, Sun WT, Yu CM, Pun SH, Underwood MJ, He GW, et al. ER stress mediates homocysteine-induced endothelial dysfunction: Modulation of IKCa and SKCa channels. Atherosclerosis 2015;242:191-98.
21. Chen GC. Deng C, Li YP. TGF-β and BMP Signaling in Osteoblast Differentiation and Bone Formation. Int J Biol Sci 2012;8:272-88.
22. Nguyen VT, Canciani B, Cirillo F, Anastasia L, Peretti GM, Mangiavini L. Effect of Chemically Induced Hypoxia on Osteogenic and Angiogenic Differentiation of Bone Marrow Mesenchymal Stem Cells and Human Umbilical Vein Endothelial Cells in Direct Coculture. Cells 2020; 9:757.
23. Lambert LM, Pipinos II, Baxter BT, Chatzizisis YS, Ryu SJ, Leighton RI, et al. In vitro measurements of hemodynamic forces and their effects on endothelial cell mechanics at the sub-cellular level. Biomicrofluidics 2018;12:064101.
24. Yin X, Liang Z, Yun Y, Pei L. Intravenous Transplantation of BMP2-Transduced Endothelial Progenitor Cells Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Rats. Cell Physiol Biochem 2015;35:2149-58.
25. da Silva RA, de Camargo Andrade AF, da Silva Feltran G, Fernandes C, de Assis RIF, Ferreira MR, et al. The role of triiodothyronine hormone and mechanically-stressed endothelial cell paracrine signalling synergism in gene reprogramming during hBMSC-stimulated osteogenic phenotype in vitro. Mol Cell Endocrinol 2018;478:151-67.
26. Illiandri, O, Sujuti H, Permatasari N, Soeharto S. Moderate Concentrations of TNF- α Induce BMP-2 Expression in Endothelial Cells. Int J Pharm Clin Res 2016;8:1666-9.
27. Fukui N, Ikeda Y, Ohnuki T, Hikita A, Tanaka S, Yamane S, et al. Proinflammatory Cytokine Tumor Necrosis Factor-α Induces Bone Morphogenetic Protein-2 in Chondrocytes via mRNA Stabilization and Transcriptional Up-regulation. J Biol Chem 2006;281:27229-41.
28. Yamamoto K, Yoshida H, Kokame K, Kaufman RJ, Mori K. Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II. J Biochem 2004;136:343-50.
29. Lee AS. The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods 2005;35:373-81.
30. Zhang HS, Nakajima H, Kato L, Gu T, Yoshitomi K, Nagai H, et al. Selective, potent blockade of the IRE1 and ATF6 pathways by 4-phenylbutyric acid analogues. Br J Pharmacol 2013;170: 822-34.
31. Yao S, Prpic V, Pan F, Wise GE. TNF-alpha upregulates expression of BMP-2 and BMP-3 genes in the rat dental follicle--implications for tooth eruption. Connect Tissue Res 2010;51:59-66.
32. McBride SH, McKenzie JA, Bedrick BS, Kuhlmann P, Pasteris JD, Rosen V, et al. Long bone structure and strength depend on BMP2 from osteoblasts and osteocytes, but not vascular endothelial cells. PLoS One 2014;9:e96862.
33. Beederman M, Lamplot JD, Nan G, Wang J, Liu X, Yin L, et al. BMP signaling in mesenchymal stem cell differentiation and bone formation. J Biomed Sci Eng 2013;6:32-52.
34. Dyer LA, Pi X, Patterson C. The role of BMPs in endothelial cell function and dysfunction. Trends Endocrinol Metab 2014;25:472-80.
35. Majka S, Hagen M, Blackwell T, Harral J, Johnson JA, Gendron R, et al. Physiologic and molecular consequences of endothelial Bmpr2 mutation. Respir Res 2011;12:84.
36. Xiao C, Giacca A, Lewis GF. Sodium phenylbutyrate, a drug with known capacity to reduce endoplasmic reticulum stress, partially alleviates lipid-induced insulin resistance and beta-cell dysfunction in humans. Diabetes 2011;60:918-24.
37. Perlmutter DH. Chemical chaperones: a pharmacological strategy for disorders of protein folding and trafficking. Pediatr Res 2002;52:832-6.
38. Illiandri O. The Role of 4-PBA on TNF-alpha related Apoptosis on Human Vein Endothelial Cells. Bangladesh J Med Sci 2019;18: 391-4.
39. Wu S, Gao X, Yang S, Meng M, Yang X, Ge B. The role of endoplasmic reticulum stress in endothelial dysfunction induced by homocysteine thiolactone. Fundam Clin Pharmacol 2015;29:252-9.
40. Zuo WH, Zeng P, Chen X, Lu YJ, Li A, Wu JB. Promotive effects of bone morphogenetic protein 2 on angiogenesis in hepatocarcinoma via multiple signal pathways. Sci Rep 2016;6:37499.
41. Spitler KM, Matsumoto T, Webb RC. Suppression of endoplasmic reticulum stress improves endothelium-dependent contractile responses in aorta of the spontaneously hypertensive rat. Am J Physiol Heart Circ Physiol 2013;305:H344-53.
42. Spitler KM, Webb RC. CHBPR: Endoplasmic Reticulum Stress Contributes to Aortic Stiffening via pro-Apoptotic and Fibrotic Signaling Mechanisms. Hypertension 2014;63:e40-5.
43. Ivanova EA, Orekhov AN. The Role of Endoplasmic Reticulum Stress and Unfolded Protein Response in Atherosclerosis. Int J Mol Sci 2016;17:193.
| Files | ||
| Issue | Vol 59, No 2 (2021) | |
| Section | Articles | |
| DOI | https://doi.org/10.18502/acta.v59i2.5573 | |
| Keywords | ||
| Bone morphogenetic protein-2 Endoplasmic reticulum stress Endothelial cells Small chain fatty acid Tumor necrosis factor-α | ||
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How to Cite
1.
Illiandri O. Small Chain Fatty Acid Phenylbutyric Acid Alleviated Inflammation-Induced Endoplasmic Reticulum Stress in Endothelial Cells. Acta Med Iran. 2021;59(2):79-85.
