Journal
JOURNAL OF INTERNAL MEDICINE
Volume 279, Issue 5, Pages 477-484Publisher
WILEY
DOI: 10.1111/joim.12461
Keywords
arginase; cholesterol; endothelium-dependent vasodilatation; familial hypercholesterolaemia; intervention; nitric oxide
Categories
Funding
- Swedish Research Council Medicine [10857, 7137]
- Swedish Heart and Lung Foundation
- Stockholm County Council (ALF)
- Karolinska Institutet/Stockholm County Council Strategic Cardiovascular Programme
- King Gustav V and Queen Victoria Foundation
- Knut and Alice Wallenberg Foundation
- Novo Nordisk Foundation
- Novo Nordisk Fonden [NNF14OC0010417, NNF15OC0015992] Funding Source: researchfish
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BackgroundElevated 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). Methods and resultsEndothelial 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-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. ConclusionArginase 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.
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