Table 2 The effects of arginase inhibitors against cardiovascular diseases.

From: Arginase: shedding light on the mechanisms and opportunities in 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]

  1. 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.
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