HuangqiGuizhiWuwu Decoction Prevents Vascular Dysfunction in Diabetes via Inhibition of Endothelial Arginase 1

Abstract

Hyperglycemia induces vascular endothelial dysfunction, which contributes to the development of vascular complication of diabetes. A classic prescription of traditional medicine, HuangqiGuizhiWuwu Decoction (HGWWD) has been used for the treatment of various cardiovascular and cerebrovascular diseases, which all are related with vascular pathology. The present study investigated the effect of HGWWD treatment in streptozocin (STZ)-induced vascular dysfunction in mouse models. In vivo studies were performed using wild type mice as well as arginase 1 knockout specific in endothelial cells (EC-A1 −/−) of control mice, diabetes mice and diabetes mice treated with HGWWD (60 g crude drugs/kg/d) for 2 weeks. For in vitro studies, aortic tissues were treated with mice serum containing HGWWD with or without adenoviral arginase 1 (Ad-A1) transduction in high glucose (HG) medium. We found that HGWWD treatment restored STZ-induced impaired mean velocity and pulsatility index of mouse left femoral arteries, aortic pulse wave velocity and vascular endothelial relaxation accompanied by elevated NO production in the aorta and plasma, as well as reduced endothelial arginase activity and aortic arginase 1 expression. The protective effect of HGWWD is reversed by an inhibitor of nitric oxide synthesis. Meanwhile, the preventive effect of serum containing HGWWD in endothelial vascular dysfunction is completely blocked by Ad-A1 transduction in HG incubated aortas. HGWWD treatment further improved endothelial vascular dysfunction in STZ induced EC-A1 −/− mice. This study demonstrates that HGWWD improved STZ-induced vascular dysfunction through arginase 1-NO signaling, specifically targeting endothelial arginase 1.

Arginine and Endothelial Function

“…This mechanism has emerged as an essential factor underlying impaired endothelial functions [ 68 , 69 ]. Specifically, an increased arginase activity has been associated with endothelial dysfunction in a number of experimental models of hypertension, atherosclerosis, diabetes, and aging [ 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 ].…”

Arginase: shedding light on the mechanisms and opportunities in cardiovascular diseases

“…Analysis of forearm blood flow in patients with T2DM showed that arginase inhibition can ameliorate endothelium-dependent vasorelaxation, which is maintained after glucose optimization [ 9 ]. ARG1 inhibition can ameliorate streptozocin-induced vascular dysfunction through increased NO production [ 126 ]. Studies of the retinal arterioles from diabetic pigs have shown that early type 1 diabetes can increase the arginase activity, thereby impairing endothelium-dependent NOS-mediated dilation of retinal arterioles during diabetes, while arginase blockade leads to the opposite results [ 127 ].…”

Arginase: Biological and Therapeutic Implications in Diabetes Mellitus and Its Complications

“…In HFD-induced obese mice, SC treatment remarkably inhibits HFD-induced increases in arginase activity and weights of liver and visceral fat tissue in a dose-dependent manner to reduce hepatic lipid metabolism and systemic adiposity via the suppression of hepatic arginase [ 182 ]. HuangqiGuizhiWuwu Decoction (HGWWD), commonly used for the treatment of diverse cardiovascular and cerebrovascular diseases in mice, was reported to lessen STZ-induced impairment of velocity and pulsatility of left femoral arteries; aortic pulse wave velocity and vascular relaxation enhance NO production in the aorta and plasma, as well as blunt endothelial arginase activity and aortic ARG1 expression [ 183 ]. In the type 1 DN mice model, Xiao-Shen-Formula (XSF) treatment improved STZ-induced renal hyper-filtration, glomerulosclerosis, and renal microvascular remodeling and prevented the increased of oxidative stress and inflammatory cytokines releases by ablating the increased levels of ARG2 protein and arginase activity, which was comparable to that of ABH treatment alone [ 184 ].…”