Julia Hwang

Background: Diabetes mellitus is the fifth most common cause of death in the world.²  Type 1 Diabetes is an autoimmune condition where pancreatic beta cells are destroyed, leaving the body unable to produce insulin.¹ Diabetics are 2-3 times more likely to develop cardiovascular diseases, and 80% of diabetic fatalities are due to cardiovascular complications.¹ The progression of diabetic cardiomyopathy is irreversible and there is currently no cure for type 1 diabetes.^4,3 There is no drug proven to be therapeutic for endothelial cell damage for diabetes.³ The etiology of diabetes is generally understood, but the intricate interplay between an individual’s immune system, genetics, and environment complicates identification of specific causes and treatments of the disease.³

Objective: The therapeutic effect of Protein C and its interaction with Y-box binding protein in diabetic cardiomyopathy induced by endothelial damage was investigated in this narrative review.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2023 using these keywords: “Protein C”, “Type 1 diabetes”, “YB-1”, and “oxidative stress”.

Results: Data collected from control and STEMI patients show that those with stress induced hyperglycemia had lower pre- and post-procedural TIMI flow, higher incidence of large thrombus burden, and higher incidence of distal embolization. ⁵ Experiments involving AC16 cells treated with adenoviruses expressing KLF5 showed that overexpression of KLF5 resulted in increased O2- formation compared to control cells. ⁶ Diabetic cardiomyocytes were also shown to have increased expression of KLF5, and suppression of KLF5 alleviated symptoms of diabetic cardiomyopathy. ⁶ In cardiac myocytes, overexpression of YB1 resulted in increased cell viability and reduced levels of inflammatory markers in response to injury caused by H2O2. ⁷ Cell viability and inflammatory markers were improved in cells with YB1 knocked down via siYB1 transfection. ⁷ To observe the expression of YB-1 in diabetics, immunoblotting was performed on cardiac cells of diabetes-induced mice. ⁸ Increased YB-1 phosphorylation and YB-1 downregulation was observed in the hearts of diabetic mice. ⁸ Treating diabetic mice with activated protein C resulted in improved cardiac function and reduced expression levels of inflammatory markers, but these benefits were contingent on the presence of YB-1. ⁴

Conclusions: Hyperglycemia plays a contributory role in the progression of diabetic cardiomyopathy through oxidative stress in cardiac cells. YB-1 exhibits protective functions in cardiac myocytes undergoing oxidative stress. YB-1 levels are abnormal in diabetic cardiac cells. Protein C improves cardiac function in cardiomyocytes but only in the presence of YB-1. These findings suggest that targeting Protein C and YB-1 may represent a promising therapeutic strategy for managing diabetic cardiomyopathy.

Works cited:

1. Sobczak AIS, Stewart AJ. Coagulatory Defects in Type-1 and Type-2 Diabetes. Int J Mol Sci. 2019;20(24):6345. Published 2019 Dec 16. doi:10.3390/ijms20246345
2. Vaidya AR, Wolska N, Vara D, Mailer RK, Schröder K, Pula G. Diabetes and Thrombosis: A Central Role for Vascular Oxidative Stress. Antioxidants (Basel). 2021;10(5):706. Published 2021 Apr 29. doi:10.3390/antiox10050706
3. DiMeglio LA, Evans-Molina C, Oram RA. Type 1 diabetes. Lancet. 2018;391(10138):2449-2462. doi:10.1016/S0140-6736(18)31320-5
4. Zhong X, Wang T, Xie Y, et al. Activated Protein C Ameliorates Diabetic Cardiomyopathy viaModulating OTUB1/YB-1/MEF2B Axis. Front Cardiovasc Med. 2021;8:758158. Published 2021 Oct 29. doi:10.3389/fcvm.2021.758158
5. Stalikas N, Papazoglou AS, Karagiannidis E, et al. Association of stress induced hyperglycemia with angiographic findings and clinical outcomes in patients with ST-elevation myocardial infarction.Cardiovasc Diabetol. 2022;21(1):140. Published 2022 Jul 26. doi:10.1186/s12933-022-01578-6
6. Kyriazis ID, Hoffman M, Gaignebet L, et al. KLF5 Is Induced by FOXO1 and Causes Oxidative Stress and Diabetic Cardiomyopathy.Circ Res. 2021;128(3):335-357. doi:10.1161/CIRCRESAHA.120.316738
7. Wang S, He F, Li Z, Hu Y, Huangfu N, Chen X. YB1 protects cardiac myocytes against H2O2‑induced injury via suppression of PIAS3 mRNA and phosphorylation of STAT3.Mol Med Rep. 2019;19(6):4579-4588. doi:10.3892/mmr.2019.10119