The importance of arginase for vascular dysfunction in patients with glucose and lipid abnormalities

University dissertation from Stockholm : Karolinska Institutet, Dept of Medicine, Solna

Abstract: Introduction: Endothelial dysfunction is one important mediator behind atherosclerosis. Maintained bioavailability of nitric oxide (NO) is critical to keep the fragile balance of endothelial function. Reduced NO arise from reduced production or increased elimination of NO. Arginase is an enzyme which metabolizes the substrate, L-arginine, which is used to produce NO. By competitive inhibition arginase may result in reduced NObioavailability. Several risk factors for atherosclerosis such as diabetes mellitus and hypercholesterolemia are known to upregulate arginase expression and activity. Furthermore, experimental research has demonstrated beneficial effects of arginase inhibition. However, the functional significance of arginase in regulation of endothelial dysfunction in patients with cardiovascular disease is unknown. Aim: To evaluate the significance of arginase inhibition on endothelial function in patients with glucose and lipid abnormalities. Study I: Forearm blood flow was determined during the administration of serotonin and sodium-nitroprusside to evaluate endothelium-dependent (EDV) and endothelium-independent (EIDV) vasodilatation, respectively, before and after 120 minutes intra-arterial (i.a.) administration of the arginase inhibitor Nω- hydroxy-L-arginine (nor-NOHA) in patients with coronary artery disease (CAD) with and without type 2 diabetes mellitus and in control subjects. Administration of nor-NOHA increased EDV in patients with CAD and diabetes and in patients with CAD alone via a NOS-dependent mechanism. Nor-NOHA did not affect EDV in control subjects. EIDV increased slightly in the CAD and diabetes group following nor-NOHA. Study II: Microvascular endothelial function was evaluated using laser Doppler flowmetry before and after 120 minutes i.a administration of nor-NOHA. EDV was reduced in subjects with type 2 diabetes mellitus and microvascular dysfunction compared to healthy subjects. Administration of nor-NOHA reversed the impairment of microvascular endothelial function in the diabetes group, but not in the control group. The levels of amino acids reflecting arginase relative activity compared to NO synthase were significantly higher in subjects with diabetes mellitus, suggesting a higher arginase activity in this group. Study III: Flow-mediated vasodilatation (FMD) of the brachial artery was evaluated in patients with CAD without and with type 2 diabetes mellitus before and after 20 minutes of forearm ischemia and 20 minutes of reperfusion in a cross-over protocol randomized to either nor-NOHA or NaCl. FMD was reduced in CAD patients following ischemia-reperfusion (IR) and administration of NaCl. Administration of norNOHA prevented the decrease in FMD after IR. In the group with CAD and diabetes, FMD following IR was significantly greater during administration of nor-NOHA than during administration of NaCl. Study IV: EDV and EIDV was determined in patients with familial hypercholesterolemia during relative low and high cholesterol levels compared to healthy control subjects before and after arginase inhibition. Baseline EDV did not differ between the groups. All groups increased their EDV in response to norNOHA. The improvement in EDV was greater among patients with familial hypercholesterolemia subjects regardless of their cholesterol level or statins use. EIDV was not affected by nor-NOHA. Conclusions: Collectively, these results demonstrate the importance of arginase for the regulation of endothelial function in patients with CAD, type 2 diabetes mellitus, and hypercholesterolemia. Arginase is a promising therapeutic target in the future treatment of endothelial dysfunction in patients with CAD, type 2 diabetes mellitus, or hypercholesterolemia.

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