Formononetin ameliorates high glucose‑induced endothelial dysfunction by inhibiting the JAK/STAT signaling pathway

Zhou,Zhen; Zhou,Xinjian; Dong,Youhong; Li,Mingyi; Xu,Yancheng

doi:10.3892/mmr.2019.10512

Formononetin ameliorates high glucose‑induced endothelial dysfunction by inhibiting the JAK/STAT signaling pathway

Authors:
- Zhen Zhou
- Xinjian Zhou
- Youhong Dong
- Mingyi Li
- Yancheng Xu
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Affiliations: Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China, Department of Endocrinology, Xiangyang First People's Hospital Affiliated to Hubei University of Medicine, Xiangyang, Hubei 441000, P.R. China, Department of Oncology, Xiangyang First People's Hospital Affiliated to Hubei University of Medicine, Xiangyang, Hubei 441000, P.R. China
Published online on: July 19, 2019 https://doi.org/10.3892/mmr.2019.10512
Pages: 2893-2901

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Abstract

High glucose‑induced endothelial Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is associated with the development and progression of the vascular complications of diabetes. The present study aimed to investigate whether formononetin, a biologically active compound isolated from Astragalus membranaceus (Fisch.) Bge, was able to regulate the JAK/STAT signaling pathway, improving endothelial function. In the present study, formononetin was identified to act as a JAK2 inhibitor, similarly to tyrphostin AG 490 (AG490), by significantly inhibiting the phosphorylation and the mRNA expression levels of JAK2 and STAT in HUVECs exposed to high glucose levels. In addition, formononetin and AG490 improved the viability of HUVECs and inhibited the protein expression levels of caspase‑3. Furthermore, formononetin and AG490 attenuated the inflammatory response in HUVECs by downregulating the protein and mRNA expression levels of interleukin (IL)‑1β and intercellular adhesion molecule 1 (ICAM‑1). Formononetin and AG490 also restored nitric oxide (NO) synthesis in HUVECs. Notably, formononetin was able to reverse the abnormal levels of phosphorylated (p)‑JAK2, p‑STAT3, IL‑1β, ICAM‑1 and NO induced by cotreatment with high glucose and IL‑6, an agonist of the JAK/STAT signaling pathway. Additionally, the present results suggested that formononetin restored phenylephrine‑mediated contraction and acetylcholine‑induced relaxation in aortic tissues of rats fed a high‑glucose diet, in a dose‑dependent manner. Collectively, formononetin could improve endothelial function under glucose stress in vivo and in vitro, suggesting that formononetin may represent a novel potential therapeutic compound to treat diabetic vascular complications.

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1	Solomon CG: Reducing cardiovascular risk in type 2 diabetes. N Engl J Med. 348:457–459. 2003. View Article : Google Scholar : PubMed/NCBI
2	Chatterjee S, Khunti K and Davies MJ: Type 2 diabetes. Lancet. 389:2239–2251. 2017. View Article : Google Scholar : PubMed/NCBI
3	Paneni F, Beckman JA, Creager MA and Cosentino F: Diabetes and vascular disease: Pathophysiology, clinical consequences, and medical therapy: Part I. Eur Heart J. 34:2436–2443. 2013. View Article : Google Scholar : PubMed/NCBI
4	Garber AJ: Diabetes and vascular disease. N Engl J Med. 2:1–5. 1990.
5	Murea M, Ma L and Freedman BI: Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications. Rev Diabet Stud. 9:6–22. 2012. View Article : Google Scholar : PubMed/NCBI
6	Martinon F, Burns K and Tschopp J: The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 10:417–426. 2002. View Article : Google Scholar : PubMed/NCBI
7	Hink U, Tsilimingas N, Wendt M and Münzel DT: Mechanisms underlying endothelial dysfunction in diabetes mellitus: Therapeutic implications. Treat Endocrinol. 2:293–304. 2003. View Article : Google Scholar : PubMed/NCBI
8	Peng H, Hong S, Li P, Li J, Zhou X and Zhang L: High glucose concentration increases the MAPK and TGF-beta-2 expression in cultured P38 human umbilical vein endothelial cells. Basic & Clinical Medicine. 27:pp. 169–173. 2007, http://en.cnki.com.cn/Article_en/CJFDTOTAL-JCYL200702010.htm
9	Takaishi H, Taniguchi T, Takahashi A, Ishikawa Y and Yokoyama M: High glucose accelerates MCP-1 production via p38 MAPK in vascular endothelial cells. Biochem Biophys Res Commun. 305:122–128. 2003. View Article : Google Scholar : PubMed/NCBI
10	Barr EL, Zimmet PZ, Welborn TA, Jolley D, Magliano DJ, Dunstan DW, Cameron AJ, Dwyer T, Taylor HR, Tonkin AM, et al: Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: The Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Circulation. 116:151–157. 2007. View Article : Google Scholar : PubMed/NCBI
11	Kisseleva T, Bhattacharya S, Braunstein J and Schindler CW: Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene. 285:1–24. 2002. View Article : Google Scholar : PubMed/NCBI
12	Rawlings JS, Rosler KM and Harrison DA: The JAK/STAT signaling pathway. J Cell Sci. 117:1281–1283. 2004. View Article : Google Scholar : PubMed/NCBI
13	Manea SA, Manea A and Heltianu C: Inhibition of JAK/STAT signaling pathway prevents high-glucose-induced increase in endothelin-1 synthesis in human endothelial cells. Cell Tissue Res. 340:71–79. 2010. View Article : Google Scholar : PubMed/NCBI
14	Marrero MB, Banes-Berceli AK, Stern DM and Eaton DC: Role of the JAK/STAT signaling pathway in diabetic nephropathy. Am J Physiol Renal Physiol. 290:F762–F768. 2006. View Article : Google Scholar : PubMed/NCBI
15	Godefroit P, Hai S, Yu T and Lauters P: New hadrosaurid dinosaurs from the uppermost Cretaceous of northeastern China. Acta Palaeontol Polonica. 53:47–74. 2008. View Article : Google Scholar
16	Tong Y and Hou H: Effects of Huangqi Guizhi Wuwu Tang on diabetic peripheral neuropathy. J Altern Complement Med. 12:506–509. 2006. View Article : Google Scholar : PubMed/NCBI
17	Sun T, Cao L, Ping NN, Wu Y, Liu DZ and Cao YX: Formononetin upregulates nitric oxide synthase in arterial endothelium through estrogen receptors and MAPK pathways. J Pharm Pharmacol. 68:342–351. 2016. View Article : Google Scholar : PubMed/NCBI
18	Wu J, Ke X, Ma N, Wang W, Fu W, Zhang H, Zhao M, Gao X, Hao X and Zhang Z: Formononetin, an active compound of Astragalus membranaceus (Fisch) Bunge, inhibits hypoxia-induced retinal neovascularization via the HIF-1α/VEGF signaling pathway. Drug Des Dev Ther. 10:3071–3081. 2016. View Article : Google Scholar
19	Wu JH, Li Q, Wu MY, Guo DJ, Chen HL, Chen SL, Seto SW, Au AL, Poon CC, Leung GP, et al: Formononetin, an isoflavone, relaxes rat isolated aorta through endothelium-dependent and endothelium-independent pathways. J Nutr Biochem. 21:613–620. 2010. View Article : Google Scholar : PubMed/NCBI
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
21	Cosentino F, Hishikawa K, Katusic ZS and Lüscher TF: High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation. 96:25–28. 1997. View Article : Google Scholar : PubMed/NCBI
22	Dabelea D and Harrod CS: Role of developmental overnutrition in pediatric obesity and type 2 diabetes. Nutr Rev. 71 (Suppl 1):S62–S67. 2013. View Article : Google Scholar : PubMed/NCBI
23	Wiernsperger NF and Bouskela E: Microcirculation in insulin resistance and diabetes: More than just a complication. Diabet Metab. 29:6S77–6S87. 2003. View Article : Google Scholar
24	Ndisang JF, Rastogi S and Vannacci A: Insulin resistance, type 1 and type 2 diabetes, and related complications 2015. J Diabetes Metab. 2015:2341352015.
25	Palmer SC, Mavridis D, Nicolucci A, Johnson DW, Tonelli M, Craig JC, Maggo J, Gray V, De Berardis G, Ruospo M, et al: Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: A meta-analysis. JAMA. 316:313–324. 2016. View Article : Google Scholar : PubMed/NCBI
26	Jermendy G: Can type 2 diabetes mellitus be considered preventable? Diabetes Res Clin Pract. 68 (Suppl 1):S73–S81. 2005. View Article : Google Scholar : PubMed/NCBI
27	Lee H, Lee D, Kang KS, Song JH and Choi YK: Inhibition of intracellular ROS accumulation by formononetin attenuates cisplatin-mediated apoptosis in LLC-PK1 cells. Int J Mol Sci. 19:2018.
28	Wang Y, Zhu Y, Gao L, Yin H, Xie Z, Wang D, Zhu Z and Han X: Formononetin attenuates IL-1β-induced apoptosis and NF-κB activation in INS-1 cells. Molecules. 17:10052–10064. 2012. View Article : Google Scholar : PubMed/NCBI
29	Qiu G, Tian W, Huan M, Chen J and Fu H: Formononetin exhibits anti-hyperglycemic activity in alloxan-induced type 1 diabetic mice. Exp Biol Med (Maywood). 242:223–230. 2017. View Article : Google Scholar : PubMed/NCBI
30	Vargha R, Bender T, Riesenhuber A, Endemann M, Kratochwill K and Aufricht C: Effects of epithelial-to-mesenchymal transition on acute stress response in human peritoneal mesothelial cells. Nephrol Dial Transplant. 23:3494–3500. 2008. View Article : Google Scholar : PubMed/NCBI
31	Schindler C, Levy DE and Decker T: JAK-STAT signaling: From interferons to cytokines. J Biol Chem. 282:20059–20063. 2007. View Article : Google Scholar : PubMed/NCBI
32	Liao JQ, Lin JQ, Zhang WJ, Xu L, Zhi XM, Lin K and Wu W: Role of JAK/STAT signaling pathway in high glucose-induced damage in human umbilical vein endothelial cells. Chin J Pathophysiol. 32:392–397. 2016.(In Chinese).
33	Budihardjo I: Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol. 15(1): 269–290. 1999. View Article : Google Scholar : PubMed/NCBI
34	Griendling KK, Sorescu D and Ushio-Fukai M: NAD(P)H oxidase: Role in cardiovascular biology and disease. Circ Res. 86:494–501. 2000. View Article : Google Scholar : PubMed/NCBI
35	Mehta JL and Li D: Identification, regulation and function of a novel lectin-like oxidized low-density lipoprotein receptor. J Am Coll Cardiol. 39:1429–1435. 2002. View Article : Google Scholar : PubMed/NCBI
36	Dinarello CA: Biologic basis for interleukin-1 in disease. Blood. 87:2095–2147. 1996.PubMed/NCBI
37	Merhi-Soussi F, Kwak BR, Magne D, Chadjichristos C, Berti M, Pelli G, James RW, Mach F and Gabay C: Interleukin-1 plays a major role in vascular inflammation and atherosclerosis in male apolipoprotein E-knockout mice. Cardiovasc Res. 66:583–593. 2005. View Article : Google Scholar : PubMed/NCBI
38	Yang L, Froio RM, Sciuto TE, Dvorak AM, Alon R and Luscinskas FW: ICAM-1 regulates neutrophil adhesion and transcellular migration of TNF-alpha-activated vascular endothelium under flow. Blood. 106:584–592. 2005. View Article : Google Scholar : PubMed/NCBI
39	Clapp BR, Hingorani AD, Kharbanda RK, Mohamed-Ali V, Stephens JW, Vallance P and MacAllister RJ: Inflammation-induced endothelial dysfunction involves reduced nitric oxide bioavailability and increased oxidant stress. Cardiovasc Res. 64:172–178. 2004. View Article : Google Scholar : PubMed/NCBI
40	Förstermann U and Sessa WC: Nitric oxide synthases: Regulation and function. Eur Heart J. 33:829–837, 837a-837d. 2012. View Article : Google Scholar : PubMed/NCBI
41	Wang X, Shaw S, Amiri F, Eaton DC and Marrero MB: Inhibition of the JAK/STAT signaling pathway prevents the high glucose-induced increase in TGF-beta and fibronectin synthesis in mesangial cells. Diabetes. 51:3505–3509. 2002. View Article : Google Scholar : PubMed/NCBI