Cardiology Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Metabolism Unit, Department of Endocrinology, Metabolism and Diabetes, Centre for Innovative Medicine, Karolinska University Hospital, Stockholm, Sweden.
J Intern Med. 2016 May;279(5):477-84. doi: 10.1111/joim.12461. Epub 2015 Dec 28.
Elevated LDL cholesterol is an important risk factor for atherosclerosis. Endothelial dysfunction, an early event in the development of atherosclerosis, is characterized by a reduction in nitric oxide (NO) bioavailability. Arginase has emerged as a key regulator of endothelial function through competition with NO synthase for the common substrate l-arginine. Arginase in endothelial cells is activated by oxidized LDL. The study aim was to investigate the importance of arginase for endothelial dysfunction in patients with familial hypercholesterolaemia (FH).
Endothelial function was evaluated in 12 patients with heterozygous FH and 12 age-matched healthy normocholesterolaemic subjects using forearm venous occlusion plethysmography. The evaluations in FH patients occurred when they were on lipid-lowering therapy and 4 weeks after withdrawal of treatment. Endothelium-dependent vasodilatation (EDV) was assessed by intrabrachial artery infusion of serotonin, and endothelium-independent dilatation was assessed by infusion of nitroprusside before and after 120 min administration of the arginase inhibitor N (ω) -hydroxy-nor-l-arginine (nor-NOHA; 0.1 mg min(-1)). In FH patients LDL cholesterol increased from 4.3 ± 0.9 mmol L(-1) at baseline to 7.6 ± 1.9 mmol L(-1) at follow-up (P < 0.001). Arginase inhibition enhanced EDV in FH patients by a similar degree independent of lipid-lowering therapy. The improvement in EDV by arginase inhibition was significantly greater in FH patients than in the control group.
Arginase inhibition results in greater improvement in endothelial function in patients with FH compared to healthy controls irrespective of their cholesterol levels. Arginase may be a promising therapeutic target for improving endothelial function in patients with hypercholesterolaemia.
升高的 LDL 胆固醇是动脉粥样硬化的一个重要危险因素。内皮功能障碍是动脉粥样硬化发展的早期事件，其特征是一氧化氮（NO）生物利用度降低。精氨酸酶通过与 NO 合酶竞争共同底物 l-精氨酸，已成为内皮功能的关键调节因子。氧化型 LDL 可激活内皮细胞中的精氨酸酶。本研究旨在探讨精氨酸酶在家族性高胆固醇血症（FH）患者内皮功能障碍中的重要性。
采用前臂静脉闭塞体积描记法评估 12 例杂合子 FH 患者和 12 例年龄匹配的健康正常胆固醇血症患者的内皮功能。FH 患者的评估在降脂治疗时进行，并在停药 4 周后进行。通过臂内动脉输注 5-羟色胺评估内皮依赖性血管舒张（EDV），通过输注硝普钠评估内皮非依赖性舒张，在 120 分钟给予精氨酸酶抑制剂 N（ω）-羟基-nor-l-精氨酸（nor-NOHA；0.1mg min(-1))前后进行。FH 患者的 LDL 胆固醇从基线时的 4.3±0.9mmol/L 升高到随访时的 7.6±1.9mmol/L（P<0.001）。无论降脂治疗如何，精氨酸酶抑制均可使 FH 患者的 EDV 得到相似程度的改善。与对照组相比，FH 患者精氨酸酶抑制后 EDV 的改善更为显著。
与健康对照组相比，精氨酸酶抑制可使 FH 患者的内皮功能得到更大程度的改善，而与胆固醇水平无关。精氨酸酶可能是改善高胆固醇血症患者内皮功能的一个有前途的治疗靶点。
