Endothelial arginase II and atherosclerosis

Abstract

Atherosclerotic vascular disease is the leading cause of morbidity and mortality in developed countries. While it is a complex condition resulting from numerous genetic and environmental factors, it is well recognized that oxidized low-density lipoprotein produces pro-atherogenic effects in endothelial cells (ECs) by inducing the expression of adhesion molecules, stimulating EC apoptosis, inducing superoxide anion formation and impairing protective endothelial nitric oxide (NO) formation. Emerging evidence suggests that the enzyme arginase reciprocally regulates NO synthase and NO production by competing for the common substrate L-arginine. As oxidized LDL (OxLDL) results in arginase activation/upregulation, it appears to be an important contributor to endothelial dysfunction by a mechanism that involves substrate limitation for endothelial NO synthase (eNOS) and NO synthesis. Additionally, arginase enhances production of reactive oxygen species by eNOS. Arginase inhibition in hypercholesterolemic (ApoE(-/-)) mice or arginase II deletion (ArgII(-/-)) mice restores endothelial vasorelaxant function, reduces vascular stiffness and markedly reduces atherosclerotic plaque burden. Furthermore, arginase activation contributes to vascular changes including polyamine-dependent vascular smooth muscle cell proliferation and collagen synthesis. Collectively, arginase may play a key role in the prevention and treatment of atherosclerotic vascular disease.

Keywords: Arginase; Atherosclerosis; Endothelial dysfunction; Endothelial nitric oxide synthase; Vascular smooth muscle cell.

Fig. 1

Arginase inhibition and its therapeutic effects on diseases. Arginase is a prime therapeutic target protein predominantly emphasized by its role in asthma, cardiovascular and carcinogenic diseases. Furthermore, its application has been extended to preventing the progress of pulmonary fibrosis and erectile dysfunction. Focusing on cardiovascular diseases, atherosclerosis, hypertension, diabetic vascular disease and ischemia/reperfusion injury are the largest drug markets, occupying at least 25% of the total therapeutic market.

Fig. 2

Arginase roles in the atherogenic pathophysiology. Endothelial NOS catalyses L-arginine to L-citrulline and nitric oxide, which is an anti-atherogenic molecule produced in the endothelium. NO has been shown to have some protective effects by inhibiting endothelial hyperpermeability, monocyte attachment, the oxidative modification of low-density lipoproteins as well as the proliferation and migration of vascular smooth muscle cells. In endothelial cells (ECs), constitutively expressed arginase shares the common substrate, L-arginine. Arginase hydrolyzes L-arginine to urea and L-ornithine that is supplied for the synthesis of polyamines and L-proline. These are commonly used for cell proliferation and collagen synthesis which increases cross-linking in the extracellular matrix, leading to increases of vascular stiffness. Furthermore, increased arginase activity stimulates eNOS monomerization by depletion of their substrates and induces superoxide production by monomerized eNOS. Augmented superoxide production quickly disrupts the redox balance in ECs and leads to endothelial dysfunction. Therefore, arginase activation directly causes atherogenic vascular disease.