Oral atorvastatin therapy restores cutaneous microvascular function by decreasing arginase activity in hypercholesterolaemic humans

Elevated low-density lipoproteins (LDLs) are associated with vascular dysfunction evident in the cutaneous microvasculature. We hypothesized that uncoupled endothelial nitric oxide synthase (NOS3) through upregulated arginase contributes to cutaneous microvascular dysfunction in hyperocholesterolaemic (HC) humans and that a statin intervention would decrease arginase activity. Five microdialysis fibres were placed in the skin of nine normocholesterolaemic (NC: LDL level 95 ± 4 mg dl^-1) and nine hypercholesterolaemic (HC: LDL: 177 ± 6 mg dl^-1) men and women before and after 3 months of systemic atrovastatin. Sites served as control, NOS inhibited, arginase inhibited, l-arginine supplemented and arginase inhibited plus l-arginine supplemented. Skin blood flow was measured while local skin heating (42°C) induced NO-dependent vasodilatation. l-NAME was infused after the established plateau in all sites to quantify NO-dependent vasodilatation. Data were normalized to maximum cutaneous vascular conductance (CVC_max). Skin samples were obtained to measure total arginase activity and arginase I and arginase II protein. Vasodilatation was reduced in hyperocholesterolaemic subjects (HC: 76 ± 2 vs. NC: 94 ± 3%CVC_max, P < 0.001) as was NO-dependent vasodilatation (HC: 43 ± 5 vs. NC: 62 ± 4%CVC_max, P < 0.001). The plateau and NO-dependent vasodilatation were augmented in HC with arginase inhibition (92 ± 2, 67 ± 2%CVC_max, P < 0.001), l-arginine (93 ± 2, 71 ± 5%CVC_max, P < 0.001) and combined treatments (94 ± 4, 65 ± 5%CVC_max, P < 0.001) but not in NC. After statin intervention (LDL: 98 ± 5 mg dl^-1) there was no longer a difference between control sites (88 ± 4, 61 ± 5%CVC_max) and localized microdialysis treatment sites (all P > 0.05). Arginase activity and protein were increased in HC skin (P < 0.05 vs. NC) and activity decreased with atrovastatin treatment (P < 0.05). Reduced NOS3 substrate availability through upregulated arginase contributes to cutaneous microvascular dysfunction in hyperocholesterolaemic humans, which is corrected with atorvastatin therapy.