title: Arginase inhibition improves endothelial function in patients with familial hypercholesterolaemia irrespective of their cholesterol levels.
abstract: BACKGROUND
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiology Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Kovamees
authors.affiliation: Cardiology Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Shemyakin
authors.affiliation: Metabolism Unit, Department of Endocrinology, Metabolism and Diabetes, Centre for Innovative Medicine, Karolinska University Hospital, Stockholm, Sweden.|KI/AZ Integrated CardioMetabolic Centre, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Eriksson
authors.affiliation: Metabolism Unit, Department of Endocrinology, Metabolism and Diabetes, Centre for Innovative Medicine, Karolinska University Hospital, Stockholm, Sweden.|KI/AZ Integrated CardioMetabolic Centre, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Angelin
authors.affiliation: Cardiology Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Pernow
mesh_terms: D000328:Adult; D001119:Arginase / Q000037:antagonists & inhibitors*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001783:Blood Flow Velocity / Q000187:drug effects; D016022:Case-Control Studies; D002784:Cholesterol / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005542:Forearm / Q000098:blood supply; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000503:physiopathology*; D008297:Male; D012701:Serotonin / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; C404735:N(omega)-hydroxynorarginine; D012701:Serotonin; D001120:Arginine; D002784:Cholesterol; D001119:Arginase
keywords: arginase; cholesterol; endothelium-dependent vasodilatation; familial hypercholesterolaemia; intervention; nitric oxide