Exercise-induced effects on atherogenesis and tryptophan catabolism via the kynurenine pathway in an HIV-associated atherosclerosis mouse model.

Abstract

A mouse model of HIV-associated atherosclerosis (Tg26^+/-ApoE^-/-) exhibited increased plaque area compared with the ApoE^-/- mouse, linked to elevated indoleamine 2,3-dioxygenase (IDO) activity. IDO catalyses the conversion of tryptophan (TRP) into kynurenine (KYN), measured by the KYN-to-TRP ratio. As a biomarker of inflammation, IDO has been implicated as a risk factor for cardiovascular disease. To investigate the effect of exercise training on atherogenesis and IDO activity in Tg26^+/-ApoE^-/- mice, nine Tg26^+/-ApoE^-/- and 18 ApoE^-/- male mice were fed an atherogenic diet and randomized into exercised or control groups. The exercised groups underwent an 8-week treadmill protocol at moderate intensity (five times per week at 60% maximum velocity). Concentrations of KYN, TRP and cytokines were measured using ELISA, immune expression by flow cytometry, and lipid profile by a biochemistry analyser. Aortas were harvested post mortem for en face analysis. Tg26^+/-ApoE^-/- mice showed ∼40% larger plaques than ApoE^-/- mice (P = 0.01), with slightly higher neutrophil (P = 0.05) and monocyte expression (P = 0.06). Plaque area was reduced by 40% in exercised ApoE^-/- mice (P = 0.04), but by only 12% in exercised Tg26^+/-ApoE^-/- animals (P = 0.85). Exercised Tg26^+/-ApoE^-/- mice showed higher IDO activity than exercised ApoE^-/- mice (58.57% ± 6.88% vs. -4.62% ± 17.20%, P = 0.01), which was positively correlated with plaque area (R = 0.99, P = 0.02). Exercised ApoE-^/- mice showed significantly lower triglyceride levels compared with exercised Tg26^+/-ApoE^-/- mice (75.8 ± 14.8 vs. 165.2 ± 43.6 mg/dL; P = 0.02). Unlike ApoE^-/- mice, moderate-intensity aerobic training did not reduce plaque area in mice with HIV-associated atherosclerosis. Moreover, exercise training appeared to increase inflammation in Tg26^+/-ApoE^-/- mice, as indicated by elevated IDO activity.