Table 2.
The effects of arginase inhibitors against cardiovascular diseases.
| Arginase inhibitor | Diseases | Model | Dosage | Effect of arginase inhibition | Refs |
|---|---|---|---|---|---|
| Chemical arginase inhibitors | |||||
| NOHA | IR injury | IR rat | 0.1 mmol/L | Decrease inflammatory cells migration in IR, prevent inflammatory cells invasion | [48] |
| Nor‐NOHA | Cardiomyopathy | Doxorubicin‐induced cardiomyopathy mice | 100 μmol/L, 12 h | Facilitate LV systolic function, lower tail BP and afterload for LV | [121] |
| PAH | Monocrotaline-induced PH rat | 100 mg/kg, 15 d | Reduce RVPsys and lung tissue remodeling | [111] | |
| Diabetic vascular disease | Retinal arterioles isolated from streptozocin-induced diabetic pigs | 0.1 mmol/L, 1.5 h | Improve dilation of retinal arterioles isolated from diabetic pigs | [127] | |
| Diabetic vascular disease | Patients with T2DM | 0.1 mg/min, 2 h | Improve microvascular endothelial function | [145] | |
| CAD | Patients with CAD | 0.1 mg/min, 20 mins | Improve flow-mediated dilatation after IR | [125] | |
| Hypertension | Spontaneously hypertensive rats | 40 mg/day, 10 weeks | Reduce systolic BP, improve vascular function, reduce artery remodeling and cardiac fibrosis | [147] | |
| Atherosclerosis | ApoE−/− mice | 10 mg/kg, 5 days/week, 9 weeks | Reduce the lipid deposition, vascular ROS, the number of macrophages and the size of atherosclerotic plaques | [148] | |
| BEC | PAH | HPAH mouse | 1 mM, 2 mL/day | Inhibit HPASMC proliferation, attenuate pulmonary vascular remodeling | [110] |
| Obesity | Obese Zucker rats | 55.6 μg/hour, 6 d | Normalize BP, restore endothelium-mediated vasodilation | [183] | |
| Atherosclerosis | ApoE−/− mice | 10 μmol/L | Restore endothelial function, reduce plaque burden and plaque load | [112] | |
| ABH | Atherosclerosis | ApoE−/− mice | 200 μg/d, 2 weeks | Increase vascular NO and decrease vascular stiffness | [112] |
| Hypertension | Male Sprague-Dawley rats | 400 μg/kg/ day, 20 d | Reduce elevated BP, revert impaired endothelial-dependent relaxation | [155] | |
| Natural arginase inhibitors | |||||
| Animo acids | Diabetic vascular disease | Patients with T2DM | 2000 mg/day, 1 month | Restore NO production levels | [161] |
| stroke | Ischemic rats | Citrulline (50 mg/kg) or ornithine (200 mg/kg) | Reduce the gait scores, infarct volume and brain edema | [162] | |
| Hypertension associated with diabetes | Streptozotocin-induced diabetic rats | Citrulline (50 mg/kg) or norvaline (50 mg/kg) or ornithine (200 mg/kg), | Reduce the elevation in diastolic BP, increase NO generation, inhibit ROS generation, restore impairment in vasoconstriction response | [184] | |
| hypertension | Hypertensive (ISIAH strain) rats | Norvaline (30 mg/kg), 7 d | Reduce the BP | [163] | |
| Hypertension | Metabolic syndrome rats | Citrulline (50 mg/kg), norvaline (50 mg/kg) and ornithine (200 mg/kg) | Reduce ROS, increase NO, restore endothelial-dependent relaxation, reduce the BP | [107] | |
| Polyphenols | Atherosclerosis | ApoE-KO mice | Pomegranate juice (31 mL/day, 10 weeks) | Promote a switch in macrophage phenotype from M1 pro-inflammatory to M2 anti-inflammatory state | [185] |
| IR injury | IR rat | EPI (1 mg/kg, 10 d) | Reduce increased nNOS isoform protein levels, maintain eNOS activity | [176] | |
| Hypertension | Old rat | PIC (30 mg/kg/day, 4 d) | Reduce BP, enhance NO production, recover endothelial dysfunction | [173] | |
ABH 2(S)-amino-6-(borono)hexanoic acid, BEC S-(2-boronoethyl)-L-cysteine, NOHA N-hydroxy-L-arginine, Nor-NOHA N-hydroxy-nor-arginine, RSV resveratrol, PIC piceatannol, EPI (-)-Epicatechin, IR ischemic reperfusion, LV left ventricle, RVPsys right ventricular systolic pressure, T2DM type 2 diabetes mellitus, CAD coronary artery disease, BP blood pressure, ROS reactive oxygen species, HPASMC human pulmonary artery smooth muscle cell, NO nitric oxide, ApoE-KO apolipoprotein E deficient, ApoE−/− apolipoprotein E-null, nNOS neuronal NO synthase, eNOS endothelial NO synthase, PH pulmonary hypertension.