Nicholas Tan

Introduction: Type II diabetes mellitus (T2DM) is a metabolic disorder affecting approximately 415 million people worldwide.^1,2  The disorder develops as the result of relative insulin deficiency due to insulin resistance or loss of function in pancreatic-ꞵ-cells.³ Cardiovascular disease (CVD) is commonly associated with diabetes, with diabetic patients having a 2-4 times greater prevalence for CVD than non-diabetic patients.^1,2 Macrovascular and microvascular complications of diabetes are main contributors to mortality and morbidity in diabetic patients, but underlying mechanisms for effective therapeutic targets have yet to be fully elucidated.² Recent studies have implicated the ureohydrolase arginase as a core player in the pathogenesis of diabetes-associated vascular dysfunction, especially impacting vascular nitric oxide (NO) production by competing with NO synthase (NOS) for their common substrate L-arginine.^4-9 Arginase can also promote L-arginine-dependent formation of collagen, leading to vascular wall stiffening. Methods: Two aortic ring assay models were utilized: one involving a high fat-high sucrose (HFHS) diet in arginase knockout mice and the other involving rat aortas incubated with T2DM patient red blood cells (RBCs).^5-8 Aortas were isolated to determine endothelium-dependent relaxation (EDR) and arginase activity. Concentrations of NO and collagen were measured using fluorescence imaging. Microvascular EDR in human T2DM patients administered arginase inhibitors was evaluated via Doppler flowmetry.⁹ These patients were age-matched with non-T2DM control subjects. Results: Mice fed a HFHS diet replicating the diabetic state exhibited impaired aortic EDR to NO when compared to those fed a normal diet.^7-8 However, EDR was significantly preserved in HFHS mice with selective deletion of vascular endothelial cell (VEC) arginase,⁷ strongly associating arginase with diabetes-induced EDR impairment. Non-arginase knockout HFHS mice exhibited decreased NO and increased collagen production, which was preserved in arginase knockout HFHS mice, indicating an association between arginase and NOS activity and vascular stiffening. Increased arginase activity within RBCs was observed following upregulation of RBC peroxynitrite associated with T2DM state.^5-6 This increase in RBC arginase activity was associated with increased VEC arginase activity leading to impaired EDR, implicating peroxynitrite as an initiator of diabetic vascular dysfunction. Arginase inhibition proved effective in improving EDR to NO in model organisms and T2DM patients.^7-9 Conclusions: Studies have implicated arginase activation as a key element in formation of diabetic vascular dysfunction. T2DM elevation of RBC peroxynitrite has been identified as a possible initiator of arginase upregulation and EDR impairment. Promising therapeutic avenues revolving around arginase have been identified, including arginase inhibition, L-arginine supplementation, RBC peroxynitrite scavenging, and selective VEC arginase deletion.

1. Petrie JR, Guzik TJ, Touyz RM. Diabetes, Hypertension, and Cardiovascular Disease: Clinical Insights and Vascular Mechanisms. Can J Cardiol. 2018;34(5):575-584. doi:10.1016/j.cjca.2017.12.005
2. Jin J, Wang X, Zhi X, Meng D. Epigenetic Regulation in Diabetic Vascular Complications. J Mol Endocrinol. 2019;63(4):R103-R115. doi:10.1530/JME-19-0170.
3. Chatterjee S, Khunti K, Davies MJ. Type 2 Diabetes [published correction appears in Lancet. 2017 Jun 3;389(10085):2192]. Lancet. 2017;389(10085):2239-2251. doi:10.1016/S0140-6736(17)30058-2
4. Caldwell RW, Rodriguez PC, Toque HA, Narayanan SP, Caldwell RB. Arginase: A Multifaceted Enzyme Important in Health and Disease. Physiol Rev. 2018;98(2):641-665. doi:10.1152/physrev.00037.2016
5. Mahdi A, Tengbom J, Alvarsson M, Wernly B, Zhou Z, Pernow J. Red Blood Cell Peroxynitrite Causes Endothelial Dysfunction in Type 2 Diabetes Mellitus via Arginase. Cells. 2020;9(7):1712. doi:10.3390/cells9071712
6. Zhou Z, Mahdi A, Tratsiakovich Y, et al. Erythrocytes From Patients With Type 2 Diabetes Induce Endothelial Dysfunction Via Arginase I. J Am Coll Cardiol. 2018;72(7):769-780. doi:10.1016/j.jacc.2018.05.052
7. Bhatta A, Yao L, Xu Z, et al. Obesity-Induced Vascular Dysfunction and Arterial Stiffening Requires Endothelial Cell Arginase 1 [published correction appears in Cardiovasc Res. 2018 Jan 1;114(1):64]. Cardiovasc Res. 2017;113(13):1664-1676. doi:10.1093/cvr/cvx164
8. Atawia RT, Toque HA, Meghil MM, et al. Role of Arginase 2 in Systemic Metabolic Activity and Adipose Tissue Fatty Acid Metabolism in Diet-Induced Obese Mice. Int J Mol Sci. 2019;20(6):1462. doi:10.3390/ijms20061462
9. Kövamees O, Shemyakin A, Checa A, et al. Arginase Inhibition Improves Microvascular Endothelial Function in Patients With Type 2 Diabetes Mellitus. J Clin Endocrinol Metab. 2016;101(11):3952-3958. doi:10.1210/jc.2016-2007