Jianpi Qinghua Formula Alleviates Diabetic Myocardial Injury Through Inhibiting JunB/c-Fos Expression

Overview

Journal Curr Med Sci

Specialty General Medicine

Date 2024 Feb 23

PMID 38393526

Authors

Lin Wang

Qing-Guang Chen

Hao Lu

Affiliations

Soon will be listed here.

Abstract

Objective: Diabetic cardiomyopathy (DCM) represents a substantial risk factor for heart failure and increased mortality in individuals afflicted with diabetes mellitus (DM). DCM typically manifests as myocardial fibrosis, myocardial hypertrophy, and impaired left ventricular diastolic function. While the clinical utility of the Jianpi Qinghua (JPQH) formula has been established in treating diabetes and insulin resistance, its potential efficacy in alleviating diabetic cardiomyopathy remains uncertain. This study aims to investigate the impact and underlying molecular mechanisms of the JPQH formula (JPQHF) in ameliorating myocardial injury in nonobese diabetic rats, specifically focusing on apoptosis and inflammation.

Methods: Wistar rats were assigned as the normal control group (CON), while Goto-Kakizaki (GK) rats were randomly divided into three groups: DM, DM treated with the JPQHF, and DM treated with metformin (MET). Following a 4-week treatment regimen, various biochemical markers related to glucose metabolism, cardiac function, cardiac morphology, and myocardial ultrastructure in GK rats were assessed. RNA sequencing was utilized to analyze differential gene expression and identify potential therapeutic targets. In vitro experiments involved high glucose to induce apoptosis and inflammation in H9c2 cells. Cell viability was evaluated using CCK-8 assay, apoptosis was monitored via flow cytometry, and the production of inflammatory cytokines was measured using quantitative real-time PCR (qPCR) and ELISA. Protein expression levels were determined by Western blotting analysis. The investigation also incorporated the use of MAPK inhibitors to further elucidate the mechanism at both the transcriptional and protein levels.

Results: The JPQHF group exhibited significant reductions in interventricular septal thickness at end-systole (IVSs) and left ventricular internal diameter at end-systole and end-diastole (LVIDs and LVIDd). JPQHF effectively suppressed high glucose-induced activation of IL-1β and caspase 3 in cardiomyocytes. Furthermore, JPQHF downregulated the expression of myocardial JunB/c-Fos, which was upregulated in both diabetic rats and high glucose-treated H9c2 cells.

Conclusion: The JPQH formula holds promise in mitigating diabetic myocardial apoptosis and inflammation in cardiomyocytes by inhibiting JunB/c-Fos expression through suppressing the MAPK (p38 and ERK1/2) pathway.

References

Dillmann W . Diabetic Cardiomyopathy. Circ Res. 2019; 124(8):1160-1162. PMC: 6578576. DOI: 10.1161/CIRCRESAHA.118.314665. View

Vecchie A, Montecucco F, Carbone F, Dallegri F, Bonaventura A . Diabetes and Vascular Disease: Is It All About Glycemia?. Curr Pharm Des. 2019; 25(29):3112-3127. DOI: 10.2174/1381612825666190830181944. View

Lorenzo-Almoros A, Cepeda-Rodrigo J, Lorenzo O . Diabetic cardiomyopathy. Rev Clin Esp (Barc). 2022; 222(2):100-111. DOI: 10.1016/j.rceng.2019.10.012. View

Jia G, Whaley-Connell A, Sowers J . Diabetic cardiomyopathy: a hyperglycaemia- and insulin-resistance-induced heart disease. Diabetologia. 2017; 61(1):21-28. PMC: 5720913. DOI: 10.1007/s00125-017-4390-4. View

Jia G, Demarco V, Sowers J . Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat Rev Endocrinol. 2015; 12(3):144-53. PMC: 4753054. DOI: 10.1038/nrendo.2015.216. View

Bugger H, Abel E . Molecular mechanisms of diabetic cardiomyopathy. Diabetologia. 2014; 57(4):660-71. PMC: 3969857. DOI: 10.1007/s00125-014-3171-6. View

Murtaza G, Virk H, Khalid M, Lavie C, Ventura H, Mukherjee D . Diabetic cardiomyopathy - A comprehensive updated review. Prog Cardiovasc Dis. 2019; 62(4):315-326. DOI: 10.1016/j.pcad.2019.03.003. View

Jia G, Hill M, Sowers J . Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity. Circ Res. 2018; 122(4):624-638. PMC: 5819359. DOI: 10.1161/CIRCRESAHA.117.311586. View

Liu Y, Han X, Cai M, Jin S, Yan Z, Lu H . Jianpi Qinghua Fomula alleviates insulin resistance via restraining of MAPK pathway to suppress inflammation of the small intestine in DIO mice. BMC Complement Med Ther. 2022; 22(1):129. PMC: 9088054. DOI: 10.1186/s12906-022-03595-0. View

10.

Tian J, Cai M, Jin S, Chen Q, Xu J, Guo Q . JianPi-QingHua formula attenuates nonalcoholic fatty liver disease by regulating the AMPK/SIRT1/NF-κB pathway in high-fat-diet-fed C57BL/6 mice. Pharm Biol. 2023; 61(1):647-656. PMC: 10101667. DOI: 10.1080/13880209.2023.2188549. View

11.

Yin M, Zhang Y, Xu S, Liu J, Sun X, Liang C . Puerarin prevents diabetic cardiomyopathy in vivo and in vitro by inhibition of inflammation. J Asian Nat Prod Res. 2018; 21(5):476-493. DOI: 10.1080/10286020.2017.1405941. View

12.

Bai Y, Han L, Qian J, Wang H . Molecular Mechanism of Against Diabetes and its Complications. Front Pharmacol. 2022; 12:780419. PMC: 8764238. DOI: 10.3389/fphar.2021.780419. View

13.

Chen X, Yu J, Shi J . Management of Diabetes Mellitus with Puerarin, a Natural Isoflavone From Pueraria lobata. Am J Chin Med. 2018; 46(8):1771-1789. DOI: 10.1142/S0192415X18500891. View

14.

Wang Y, Liu H, Zheng M, Yang Y, Ren H, Kong Y . Berberine Slows the Progression of Prediabetes to Diabetes in Zucker Diabetic Fatty Rats by Enhancing Intestinal Secretion of Glucagon-Like Peptide-2 and Improving the Gut Microbiota. Front Endocrinol (Lausanne). 2021; 12:609134. PMC: 8138858. DOI: 10.3389/fendo.2021.609134. View

15.

Xu X, Yi H, Wu J, Kuang T, Zhang J, Li Q . Therapeutic effect of berberine on metabolic diseases: Both pharmacological data and clinical evidence. Biomed Pharmacother. 2020; 133:110984. DOI: 10.1016/j.biopha.2020.110984. View

16.

El-Omar M, Yang Z, Phillips A, Shah A . Cardiac dysfunction in the Goto-Kakizaki rat. A model of type II diabetes mellitus. Basic Res Cardiol. 2004; 99(2):133-41. DOI: 10.1007/s00395-004-0440-4. View

17.

Movassat J, Bailbe D, Lubrano-Berthelier C, Picarel-Blanchot F, Bertin E, Mourot J . Follow-up of GK rats during prediabetes highlights increased insulin action and fat deposition despite low insulin secretion. Am J Physiol Endocrinol Metab. 2007; 294(1):E168-75. DOI: 10.1152/ajpendo.00501.2007. View

18.

Korkmaz-Icoz S, Lehner A, Li S, Vater A, Radovits T, Hegedus P . Mild Type 2 Diabetes Mellitus Reduces the Susceptibility of the Heart to Ischemia/Reperfusion Injury: Identification of Underlying Gene Expression Changes. J Diabetes Res. 2015; 2015:396414. PMC: 4502305. DOI: 10.1155/2015/396414. View

19.

Ding Y, Zhou Y, Ling P, Feng X, Luo S, Zheng X . Metformin in cardiovascular diabetology: a focused review of its impact on endothelial function. Theranostics. 2021; 11(19):9376-9396. PMC: 8490502. DOI: 10.7150/thno.64706. View

20.

Yang F, Qin Y, Wang Y, Meng S, Xian H, Che H . Metformin Inhibits the NLRP3 Inflammasome via AMPK/mTOR-dependent Effects in Diabetic Cardiomyopathy. Int J Biol Sci. 2019; 15(5):1010-1019. PMC: 6535781. DOI: 10.7150/ijbs.29680. View