Gycyrrhizic acid alleviates atherosclerotic lesions in rats with diabetes mellitus

Zhao,Yaodong; Li,Wei; Zhang,Daimin

doi:10.3892/mmr.2021.12395

Gycyrrhizic acid alleviates atherosclerotic lesions in rats with diabetes mellitus

Authors:
- Yaodong Zhao
- Wei Li
- Daimin Zhang
View Affiliations

Affiliations: Department of General Internal Medicine, The Fifth Affiliated Hospital of Zhengzhou University, Zhenzhou, Henan 450052, P.R. China, Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
Published online on: September 2, 2021 https://doi.org/10.3892/mmr.2021.12395
Article Number: 755
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Gycyrrhizic acid (GA), an inhibitor of high mobility group box 1 (HMGB1), inhibits inflammatory responses and is involved in the occurrence and development of several inflammation‑related diseases. However, the role of GA in the atherosclerotic lesions caused by diabetes mellitus (DM) remains unknown. In the present study, Sprague Dawley rats were selected to desi=gn a diabetic atherosclerosis (AS) model. Rats from the DM‑AS group were subsequently divided into DM‑AS, DM‑AS + GA (50 mg/kg) and DM‑AS + GA (150 mg/kg) groups. Biochemical analyzers were used to measure levels of blood glucose, fasting insulin, total cholesterol, total triglyceride, low‑density lipoprotein and high‑density lipoprotein. The number of plaques was recorded after collection of thoracic aortas from the rats. The intimal thickness of arterial tissue was detected by hematoxylin and eosin staining. The expression levels of CD68 and α‑smooth muscle actin (α‑SMA) were detected by immunohistochemistry. The expression of tumor necrosis factor‑α, interleukin (IL)‑6 and IL‑1β in the serum of the rats was detected by ELISA. The expression of fatty acid synthetase, sterol regulatory element binding protein 1C, HMGB1 and receptor for advanced glycation end products (RAGE) was detected by western blotting. Reverse transcription quantitative PCR was used to detect the mRNA expression of HMGB1 and RAGE. The results demonstrated that GA treatment could decrease the body weight, blood glucose level and biochemical parameters of AS DM rats in a dose‑dependent manner. In addition, GA decreased the intimal thickness of carotid artery and the formation of plaque in rats with diabetic AS. Furthermore, GA inhibited macrophage activation and decreased α‑SMA expression in vascular smooth muscle cells, and decreased the expression of proteins (FAS and SREBP‑1c) and inflammatory factors. Taken together, the findings from the present study demonstrated that GA may have a therapeutic effect on DM‑associated AS. This study provides a theoretical basis for the treatment of diabetic AS.

View Figures

View References

1	Guthrie RA and Guthrie DW: Pathophysiology of diabetes mellitus. Crit Care Nurs Q. 27:113–125. 2004. View Article : Google Scholar : PubMed/NCBI
2	Unnikrishnan R, Anjana RM and Mohan V: Diabetes mellitus and its complications in India. Nat Rev Endocrinol. 12:357–370. 2016. View Article : Google Scholar : PubMed/NCBI
3	Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, Colagiuri S, Guariguata L, Motala AA, Ogurtsova K, et al: Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas. (9(th) edition). Diabetes Res Clin Pract. 157:1078432019. View Article : Google Scholar : PubMed/NCBI
4	Strain WD and Paldánius PM: Diabetes, cardiovascular disease and the microcirculation. Cardiovasc Diabetol. 17:572018. View Article : Google Scholar : PubMed/NCBI
5	Kannenkeril D, Bosch A, Harazny J, Karg M, Jung S, Ott C and Schmieder RE: Early vascular parameters in the micro- and macrocirculation in type 2 diabetes. Cardiovasc Diabetol. 17:1282018. View Article : Google Scholar : PubMed/NCBI
6	Di Pino A and DeFronzo RA: Insulin resistance and atherosclerosis: Implications for insulin-sensitizing agents. Endocr Rev. 40:1447–1467. 2019. View Article : Google Scholar : PubMed/NCBI
7	Stabley JN and Towler DA: Arterial calcification in diabetes mellitus: Preclinical models and translational implications. Arterioscler Thromb Vasc Biol. 37:205–217. 2017. View Article : Google Scholar : PubMed/NCBI
8	Poznyak A, Grechko AV, Poggio P, Myasoedova VA, Alfieri V and Orekhov AN: The diabetes mellitus-atherosclerosis connection: The role of lipid and glucose metabolism and chronic inflammation. Int J Mol Sci. 21:18352020. View Article : Google Scholar : PubMed/NCBI
9	Ioachimescu AG: Diabetes and atherosclerotic cardiovascular disease. Endocrinol Metab Clin North Am. 47:xiii–xiv. 2018. View Article : Google Scholar : PubMed/NCBI
10	Zhu Y, Xian X, Wang Z, Bi Y, Chen Q, Han X, Tang D and Chen R: Research progress on the relationship between atherosclerosis and inflammation. Biomolecules. 8:802018. View Article : Google Scholar : PubMed/NCBI
11	Laakso M and Kuusisto J: Insulin resistance and hyperglycaemia in cardiovascular disease development. Nat Rev Endocrinol. 10:293–302. 2014. View Article : Google Scholar : PubMed/NCBI
12	Yahagi K, Kolodgie FD, Lutter C, Mori H, Romero ME, Finn AV and Virmani R: Pathology of human coronary and carotid artery atherosclerosis and vascular calcification in diabetes mellitus. Arterioscler Thromb Vasc Biol. 37:191–204. 2017. View Article : Google Scholar : PubMed/NCBI
13	Dryden M, Baguneid M, Eckmann C, Corman S, Stephens J, Solem C, Li J, Charbonneau C, Baillon-Plot N and Haider S: Pathophysiology and burden of infection in patients with diabetes mellitus and peripheral vascular disease: Focus on skin and soft-tissue infections. Clin Microbiol Infect. 21 (Suppl 2):S27–S32. 2015. View Article : Google Scholar : PubMed/NCBI
14	Malahfji M and Mahmarian JJ: Imaging to stratify coronary artery disease risk in asymptomatic patients with diabetes. Methodist Debakey Cardiovasc J. 14:266–272. 2018.PubMed/NCBI
15	Andersson U and Tracey KJ: HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol. 29:139–162. 2011. View Article : Google Scholar : PubMed/NCBI
16	Deng M, Scott MJ, Fan J and Billiar TR: Location is the key to function: HMGB1 in sepsis and trauma-induced inflammation. J Leukoc Biol. 106:161–169. 2019.PubMed/NCBI
17	Wang R, Wu W, Li W, Huang S, Li Z, Liu R, Shan Z, Zhang C, Li W and Wang S: Activation of NLRP3 inflammasome promotes foam cell formation in vascular smooth muscle cells and atherogenesis Via HMGB1. J Am Heart Assoc. 7:e0085962018. View Article : Google Scholar : PubMed/NCBI
18	Zhang J, Zhang L, Zhang S, Yu Q, Xiong F, Huang K, Wang CY and Yang P: HMGB1, an innate alarmin, plays a critical role in chronic inflammation of adipose tissue in obesity. Mol Cell Endocrinol. 454:103–111. 2017. View Article : Google Scholar : PubMed/NCBI
19	Ding JW, Luo CY, Wang XA, Zhou T, Zheng XX, Zhang ZQ, Yu B, Zhang J and Tong XH: Glycyrrhizin, a high-mobility group box 1 inhibitor, improves lipid metabolism and suppresses vascular inflammation in apolipoprotein e knockout mice. J Vasc Res. 55:365–377. 2018. View Article : Google Scholar : PubMed/NCBI
20	Hou S, Zhang T, Li Y, Guo F and Jin X: Glycyrrhizic acid prevents diabetic nephropathy by activating AMPK/SIRT1/PGC-1α Signaling in db/db Mice. J Diabetes Res. 2017:28659122017. View Article : Google Scholar : PubMed/NCBI
21	Zhang H, Zhang R, Chen J, Shi M, Li W and Zhang X: High Mobility Group Box1 inhibitor glycyrrhizic acid attenuates kidney injury in streptozotocin-induced diabetic rats. Kidney Blood Press Res. 42:894–904. 2017. View Article : Google Scholar : PubMed/NCBI
22	Li J, Liu X, Fang Q, Ding M and Li C: Liraglutide attenuates atherosclerosis via inhibiting ER-induced macrophage derived microvesicles production in T2DM rats. Diabetol Metab Syndr. 9:942017. View Article : Google Scholar : PubMed/NCBI
23	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
24	Shah AD, Langenberg C, Rapsomaniki E, Denaxas S, Pujades-Rodriguez M, Gale CP, Deanfield J, Smeeth L, Timmis A and Hemingway H: Type 2 diabetes and incidence of cardiovascular diseases: A cohort study in 1.9 million people. Lancet Diabetes Endocrinol. 3:105–113. 2015. View Article : Google Scholar : PubMed/NCBI
25	Haas AV and McDonnell ME: Pathogenesis of cardiovascular disease in diabetes. Endocrinol Metab Clin North Am. 47:51–63. 2018. View Article : Google Scholar : PubMed/NCBI
26	Buszman PP, Bochenek A, Konkolewska M, Trela B, Kiesz RS, Wilczyński M, Cisowski M, Krejca M, Banasiewicz-Szkróbka I, Krol M, et al: Early and long-term outcomes after surgical and percutaneous myocardial revascularization in patients with non-ST-elevation acute coronary syndromes and unprotected left main disease. J Invasive Cardiol. 21:564–569. 2009.PubMed/NCBI
27	Zhou J, Zhe R, Guo X, Chen Y, Zou Y, Zhou L and Wang Z: The Role of PPARδ Agosnist GW501516 in rats with gestational diabetes mellitus. Diabetes Metab Syndr Obes. 13:2307–2316. 2020. View Article : Google Scholar : PubMed/NCBI
28	Rani R, Dahiya S, Dhingra D, Dilbaghi N, Kaushik A, Kim KH and Kumar S: Antidiabetic activity enhancement in streptozotocin + nicotinamide-induced diabetic rats through combinational polymeric nanoformulation. Int J Nanomedicine. 14:4383–4395. 2019. View Article : Google Scholar : PubMed/NCBI
29	Moroni F, Ammirati E, Norata GD, Magnoni M and Camici PG: The role of monocytes and macrophages in human atherosclerosis, plaque neoangiogenesis, and atherothrombosis. Mediators Inflamm. 2019:74343762019. View Article : Google Scholar : PubMed/NCBI
30	Palone F, Pasquali E, Giardullo P, Stronati L, Vitali R and Mancuso M: Low dose of dipotassium glycyrrhizate counteracts atherosclerosis progression in apoe-/-female mice. J Vasc Res. 56:267–270. 2019. View Article : Google Scholar : PubMed/NCBI
31	Wang Y, Le Y, Zhao W, Lin Y, Wu Y, Yu C, Xiong J, Zou F, Dong H, Cai S and Zhao H: Short thymic stromal lymphopoietin attenuates toluene diisocyanate-induced airway inflammation and inhibits high mobility group box 1-receptor for advanced glycation end products and long thymic stromal lymphopoietin expression. Toxicol Sci. 157:276–290. 2017. View Article : Google Scholar : PubMed/NCBI
32	Brown MS and Goldstein JL: The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell. 89:331–340. 1997. View Article : Google Scholar : PubMed/NCBI
33	Chen J, Zhang J, Xu L, Xu C, Chen S, Yang J and Jiang H: Inhibition of neointimal hyperplasia in the rat carotid artery injury model by a HMGB1 inhibitor. Atherosclerosis. 224:332–339. 2012. View Article : Google Scholar : PubMed/NCBI
34	Cybulsky MI, Cheong C and Robbins CS: Macrophages and dendritic cells: Partners in atherogenesis. Circ Res. 118:637–652. 2016. View Article : Google Scholar : PubMed/NCBI