Arginase Inhibition Improves Endothelial Function in Patients With Coronary Artery Disease and Type 2 Diabetes

Study Questions:

Does inhibition of arginase activity improve endothelial function among patients with coronary artery disease (CAD) and type 2 diabetes mellitus (DM)?

Methods:

Three groups of patients were studied, including 16 patients with CAD; 16 patients with CAD and type 2 DM; and 16 patients with age-matched healthy controls. CAD was defined as a history of myocardial infarction, or significant CAD determined by coronary angiogram. Control subjects were matched for age, were on no medications, and had no history of cardiovascular disease. Endothelial function was assessed via forearm endothelial-dependent (EDV) and endothelium-independent (EIDV) vasodilation using venous occlusion plethysmography at baseline and after infusion of arginase inhibitor Nω-hydroxy-nor-L-Arginine (nor-NOHA; 0.1 mg/min). Nor-NOHA was also co-infused with the nitric oxide synthase inhibitor (L-NMMA). The expression of arginine was determined in the internal mammary artery of patients undergoing bypass surgery.

Results:

Blood pressure was similar between the three groups, and all groups were overweight. However, the control group had lower waist-to-hip ratios compared to the other groups. As expected, both fasting glucose and glycated hemoglobin were higher in the group with DM. Nor-NOHA markedly increased EDV (up to twofold) in patients with CAD and DM and patients with CAD alone (p < 0.001), but not in the control group. L-NMMA completely inhibited the increase in EDV induced by nor-NOHA. EIDV was slightly improved by nor-NOHA in the CAD and DM group. Arginase I was expressed in vascular smooth muscle cells and endothelial cells, and arginase II was expressed in endothelial cells of patients with and without DM.

Conclusions:

The investigators concluded that arginase inhibition improves endothelial function in patients with CAD and type 2 DM, suggesting that increased arginase activity may be a key factor in the development of endothelial dysfunction.

Perspective:

This is a very interesting study; furthering current understanding of endothelial function may be clinically important for identification of future therapeutic options. The hypotheses outlined in this small trial should be examined in a larger cohort.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Atherosclerotic Disease (CAD/PAD), Diet

Keywords: Coronary Artery Disease, Myocardial Infarction, Vasodilation, Overweight, Nitric Oxide Synthase, Diabetes Mellitus, Type 2, Coronary Disease, Blood Pressure, Enzyme Inhibitors, Forearm, Glucose, omega-N-Methylarginine, Cardiology, Mammary Arteries, Endothelial Cells, Fasting


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