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 with 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 versus 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.

Keywords::

• myeloperoxidase
• thiocyanate
• hypothiocyanous acid
• hypochlorous acid
• atherosclerosis
• thiol oxidation

Acknowledgments

The authors thank Drs. David Pattison and Christina Bursill for assistance with the kinetic modeling assistance and lesion analyses, respectively. This work was supported by the Australian Research Council (through the ARC Centres of Excellence: CE0561607, and Discovery Programs: DP0988311 to MJD), the Novo Nordisk Foundation (to MJD), and NIH grants RO1HL088428 and RO1NS074303 (to WFR) and R43HL095251 (to RAM).

Declaration of interest

The authors report no declarations of interest. The authors alone are responsible for the content and writing of this paper.