High Glucose Promotes Heme Oxygenase-1 Expression in Human Lung Epithelial Cellsvia Reactive Oxygen Species or TGF-β 1/PI3K/Akt Signaling Pathway _Chinese Journal of Respiratory and Critical Care Medicine

Authors：

KANGXiaowen ¹ , KONGFanwu ² , ZHANGWei ³ , WANGXinyan ¹ , HUANGKun ¹ , LIZhaoguo ¹ ,  WUXiaomei ¹

1. Department of Pulmonology, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R.China;
2. Department of Nephrology, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R.China;
3. Department of Pulmonology, The First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R.China;

Corresponding author：

WUXiaomei, Email: 15045022124@163.com

Keywords：

Heme oxygenase-1; Human lung epithelial cells; High glucose; Reactive oxygen species

DOI：

10.7507/1671-6205.201605052

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Objective To investigate the expression of heme oxygenase-1 (HO-1) by high glucose treatment in human lung epithelial A549 cells. Methods The effect of high glucose on the expression of HO-1 in A549 cells was investigated with Western blot and reverse transcription PCR. HO-1 enzymic activity and reactive oxygen species (ROS) production were investigated with enzyme-linked immunosorbent test. Results Treatment with 25 mmol/L high glucose for 0, 24 h, 48 h, 72 h and in concentrations of 5 mmol/L, 10 mmol/L, 25 mmol/L, 40 mmol/L for 48 h induced increased expression on protein and mRNA level of HO-1 in a concentration- and time-dependent manner in A549 cells. High glucose treatment increased production of ROS and transforming growth factor-β₁ (TGF-β₁) in A549 cells, which thus mediated HO-1 expression. Following the increase in HO-1 expression, the enzymatic activity of HO-1 also increased in high glucose-treated cells. Pretreatment with N-acetyl-L-cysteine (NAC) and PI3K/Akt inhibitors attenuated the high glucose-induced increased HO-1 expression. Conclusions High glucose increases ROS and TGF-β₁ production in A549 cells, which mediates HO-1 expression and increases HO-1 enzymic activity.

Citation： KANGXiaowen, KONGFanwu, ZHANGWei, WANGXinyan, HUANGKun, LIZhaoguo, WUXiaomei. High Glucose Promotes Heme Oxygenase-1 Expression in Human Lung Epithelial Cellsvia Reactive Oxygen Species or TGF-β₁/PI3K/Akt Signaling Pathway . Chinese Journal of Respiratory and Critical Care Medicine, 2017, 16(1): 40-45. doi: 10.7507/1671-6205.201605052 Copy

1.	Drummond GS, Kappas A. Chemoprevention of neonatal jaundice: potency of tin-protoporphyrin in an animal model. Science, 1982, 217(4566): 1250-1252.
2.	Rodgers PA, Stevenson DK. Developmental biology of heme oxygenase. Clin Perinatol, 1990, 17(2): 275-291.
3.	Cisowski J, Loboda A, Jozkowicz A, et al. Role of hemeoxygenase-1 in hydrogen peroxide-induced VEGF synthesis: effect of HO-1 knockout. Biochem Biophys Res Commun, 2005, 326(3): 670-676.
4.	Ferrando M, Gueron G, Elguero B, Giudice J, et al. Hemeoxygenase-1(HO-1) challenges the angiogenic switch in prostate cancer. Angiogenesis, 2011, 14(4): 467-479.
5.	Wu M, Huang J, Xu S, et al. Hemeoxygenase-1 delays programmed cell death in wheat aleurone layers by modulation of hydrogen peroxide metabolism. J Exp Bot, 2011, 62(1): 235-248.
6.	Bao W, Song F, Li X, et al. Plasma heme oxygenase-1 concentration is elevated in individuals with type 2 diabetes mellitus. PLoS One, 2010, 5(8): e12371.
7.	Miyake M, Fujimoto K, Anai S, et al. Heme oxygenase-1promotes angiogenesis in urothelial carcinoma of the urinary bladder. Oncol Rep, 2011, 25(3): 653-660.
8.	Jee SH, AOhrr H, Sull JW, et al. Fasting serum glucose level and cancer risk in Korean men and women. JAMA, 2005, 293(2): 194-202.
9.	Sato T, Takeno M, Honma K, et al. Heme oxygenase-1, a potential biomarker of chronic silicosis, attenuates silica-induced lung injury. Am J Respir Crit Care Med, 2006, 174(8): 906-914.
10.	Mateo I, Infante J, Sanchez-Juan P, et al. Serum heme oxygenase-1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease. Acta Neurol Scand, 2010, 121(2): 136-138.
11.	Miyazaki T, Kirino Y, Takeno M, et al. Serum HO-1 is useful to make differential diagnosis of secondary hemophagocytic syndrome from other similar hematological conditions. Int J Hematol, 2010, 91(2): 229-237.
12.	Susztak K, Raff AC, Schiffer M, et al. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes, 2006, 55(1): 225-233.
13.	Wu WS. The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev, 2006, 25(4): 695-705.
14.	Li H, van Berlo D, Shi T, et al. Curcumin protects against cytotoxic and inflammatory effects of quartz particles but causes oxidative DNA damage in a rat lung epithelial cell line. Toxicol Appl Pharmacol, 2008, 227(1): 115-124.
15.	Zuo L, Youtz DJ, Wold LE. Particulate matter exposure exacerbates high glucose-induced cardiomyocyte dysfunction through ROS generation. PLoS One, 2011, 6(8): e23116.
16.	Toyonaga J, Tsuruya K, Ikeda H, et al. Spironolactone inhibits hyperglycemia-induced podocyte injury by attenuating ROS production. Nephrol Dial Transplant, 2011, 26(8): 2475-2484.
17.	Bonnefont-Rousselot D, Bastard JP, Jaudon MC, et al. Consequences of the diabetic status on the oxidant/antioxidant balance. Diabetes Metab, 2000, 26(3): 163-176.
18.	Inoguchi T, Li P, Umeda F, et al. High glucose level and free fatty acid stimulate reactive oxygen species production throughprotein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes, 2000, 49(11): 1939-1945.
19.	Singh R, Barden A, Mori T, et al. Advanced glycation endproducts: a review. Diabetologia, 2001, 44(2): 129-146.
20.	Alisson-Silva F, Freire-de-Lima L, Donadio JL, et al. Increase of O-glycosylated oncofetal fibronectin in high glucose-induced epithelial-mesenchymal transition of cultured human epithelial cells. PLoS One, 2013, 8(4): e60471.
21.	李军涛, 张恒伟, 郭旭辉, 等. 高糖对人乳腺癌细胞体外侵袭能力的影响. 中华医学杂志, 2013, 93(2): 89-92.
22.	Li W, Ma Q, Li J, et al. Hyperglycemia enhances the invasive and migratory activity of pancreatic cancer cells via hydrogen peroxide. Oncol Rep, 2011, 25(5): 1279-1287.

1. Drummond GS, Kappas A. Chemoprevention of neonatal jaundice: potency of tin-protoporphyrin in an animal model. Science, 1982, 217(4566): 1250-1252.
2. Rodgers PA, Stevenson DK. Developmental biology of heme oxygenase. Clin Perinatol, 1990, 17(2): 275-291.
3. Cisowski J, Loboda A, Jozkowicz A, et al. Role of hemeoxygenase-1 in hydrogen peroxide-induced VEGF synthesis: effect of HO-1 knockout. Biochem Biophys Res Commun, 2005, 326(3): 670-676.
4. Ferrando M, Gueron G, Elguero B, Giudice J, et al. Hemeoxygenase-1(HO-1) challenges the angiogenic switch in prostate cancer. Angiogenesis, 2011, 14(4): 467-479.
5. Wu M, Huang J, Xu S, et al. Hemeoxygenase-1 delays programmed cell death in wheat aleurone layers by modulation of hydrogen peroxide metabolism. J Exp Bot, 2011, 62(1): 235-248.
6. Bao W, Song F, Li X, et al. Plasma heme oxygenase-1 concentration is elevated in individuals with type 2 diabetes mellitus. PLoS One, 2010, 5(8): e12371.
7. Miyake M, Fujimoto K, Anai S, et al. Heme oxygenase-1promotes angiogenesis in urothelial carcinoma of the urinary bladder. Oncol Rep, 2011, 25(3): 653-660.
8. Jee SH, AOhrr H, Sull JW, et al. Fasting serum glucose level and cancer risk in Korean men and women. JAMA, 2005, 293(2): 194-202.
9. Sato T, Takeno M, Honma K, et al. Heme oxygenase-1, a potential biomarker of chronic silicosis, attenuates silica-induced lung injury. Am J Respir Crit Care Med, 2006, 174(8): 906-914.
10. Mateo I, Infante J, Sanchez-Juan P, et al. Serum heme oxygenase-1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease. Acta Neurol Scand, 2010, 121(2): 136-138.
11. Miyazaki T, Kirino Y, Takeno M, et al. Serum HO-1 is useful to make differential diagnosis of secondary hemophagocytic syndrome from other similar hematological conditions. Int J Hematol, 2010, 91(2): 229-237.
12. Susztak K, Raff AC, Schiffer M, et al. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes, 2006, 55(1): 225-233.
13. Wu WS. The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev, 2006, 25(4): 695-705.
14. Li H, van Berlo D, Shi T, et al. Curcumin protects against cytotoxic and inflammatory effects of quartz particles but causes oxidative DNA damage in a rat lung epithelial cell line. Toxicol Appl Pharmacol, 2008, 227(1): 115-124.
15. Zuo L, Youtz DJ, Wold LE. Particulate matter exposure exacerbates high glucose-induced cardiomyocyte dysfunction through ROS generation. PLoS One, 2011, 6(8): e23116.
16. Toyonaga J, Tsuruya K, Ikeda H, et al. Spironolactone inhibits hyperglycemia-induced podocyte injury by attenuating ROS production. Nephrol Dial Transplant, 2011, 26(8): 2475-2484.
17. Bonnefont-Rousselot D, Bastard JP, Jaudon MC, et al. Consequences of the diabetic status on the oxidant/antioxidant balance. Diabetes Metab, 2000, 26(3): 163-176.
18. Inoguchi T, Li P, Umeda F, et al. High glucose level and free fatty acid stimulate reactive oxygen species production throughprotein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes, 2000, 49(11): 1939-1945.
19. Singh R, Barden A, Mori T, et al. Advanced glycation endproducts: a review. Diabetologia, 2001, 44(2): 129-146.
20. Alisson-Silva F, Freire-de-Lima L, Donadio JL, et al. Increase of O-glycosylated oncofetal fibronectin in high glucose-induced epithelial-mesenchymal transition of cultured human epithelial cells. PLoS One, 2013, 8(4): e60471.
21. 李军涛, 张恒伟, 郭旭辉, 等. 高糖对人乳腺癌细胞体外侵袭能力的影响. 中华医学杂志, 2013, 93(2): 89-92.
22. Li W, Ma Q, Li J, et al. Hyperglycemia enhances the invasive and migratory activity of pancreatic cancer cells via hydrogen peroxide. Oncol Rep, 2011, 25(5): 1279-1287.

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High Glucose Promotes Heme Oxygenase-1 Expression in Human Lung Epithelial Cellsvia Reactive Oxygen Species or TGF-β₁/PI3K/Akt Signaling Pathway

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