Thiocyanate supplementation decreases atherosclerotic plaque in mice expressing human myeloperoxidase

Abstract

Elevated levels of the heme enzyme myeloperoxidase (MPO) are associated with adverse cardiovascular outcomes. MPO predominantly catalyzes formation of the oxidants hypochlorous acid (HOCl) from Cl−, and hypothiocyanous acid (HOSCN) from SCN−, with these anions acting as competitive substrates. HOSCN is a less powerful and more specific oxidant than HOCl, and selectively targets thiols; such damage is largely reversible, unlike much HOCl-induced damage. We hypothesized that increased plasma SCN−, and hence HOSCN formation instead of HOCl, may decrease artery wall damage. This was examined using high-fat fed atherosclerosis-prone LDLR−/− mice transgenic for human MPO, with and without SCN− (10 mM) added to drinking water. Serum samples, collected fortnightly, were analyzed for cholesterol, triglycerides, thiols, MPO and SCN−; study-long exposure was calculated by area under the curve (AUC). Mean serum SCN− concentrations were elevated in the supplemented mice (200-320 μM) relative to controls (<120 μM). Normalized aortic root plaque areas at sacrifice were 26% lower in the SCN−-supplemented mice compared to controls (P=0.0417), but plaque morphology was not appreciably altered. Serum MPO levels steadily increased in mice on the high-fat diet, however, comparison of SCN−- supplemented vs. control mice showed no significant changes in MPO protein, cholesterol or triglyceride levels; thiol levels were decreased in supplemented mice at one time-point. Plaque areas increased with higher cholesterol AUC (r=0.4742; P=0.0468), and decreased with increasing SCN− AUC (r=−0.5693; P=0.0134). These data suggest that increased serum SCN− levels, which can be achieved in humans by dietary manipulation, may decrease atherosclerosis burden.

The Role of Myeloperoxidase in Biomolecule Modification, Chronic Inflammation, and Disease

“…This may arise from upregulation of TrxR within the lung tissue, which can detoxify HOSCN, and hence preserve GSH (42). Similarly, supplementing atherosclerosis-prone mice, which overexpress human MPO, with SCNresulted in a marked decrease in plaque area (164). These protective effects have been detected at SCNlevels that can be readily achieved and tolerated in humans (164), but more work is needed to assess the mechanism(s) involved, and particularly whether this arises from an alteration in HOCl levels in these animals.…”

Biochemical mechanisms and therapeutic potential of pseudohalide thiocyanate in human health

“…SCN − dose-dependently decreased cholesterol deposition in the aorta and kidneys of thyroidectomized rabbits given 0, 20 or 60 mg kg −1 potassium SCN − and 300 mg kg −1 cholesterol daily [56]. Giving 10 mM sodium SCN − in drinking water to LDL receptor-knockout, MPO-463G transgenic mice (an established proatherogenic model [168]) increased plasma SCN − >2-fold over baseline and decreased aortic arch plaque area by 26% compared to control [16]. Together these studies suggest SCN − may protect against adverse cardiovascular outcomes, in agreement with recent clinical research [18].…”

“…The role of SCN − in airway host defense was underscored by observations of deficient or dysregulated SCN − efflux in the epithelial secretions of CF cells which impaired the cells’ ability to kill bacteria [12,13]. Recent and ongoing research with mouse models has borne out the hypothesis that SCN − may be a useful intervention for resolving infection and inflammation [14-16]. Similarly, recent clinical data supports the hypothesis of a beneficial role for SCN − in human health [17,18].…”

Low-density lipoprotein modified by myeloperoxidase oxidants induces endothelial dysfunction

“…Similarly, serum SCN - levels in smokers correlate with a higher deposition of oxidised LDL and fatty streak formation in the arteries [34] , [35] . However, supplementation of transgenic, atherosclerosis-prone, mice that over-express human MPO, with SCN - resulted in a decreased extent of lesion formation [36] . The reactivity of HOCl and HOSCN are strikingly different [37] , which results in the formation of modified LDL particles that have distinct cellular effects [27] , [38] , [39] .…”