Efeito do treinamento físico sobre a aterogênese e o catabolismo do triptofano pela via da quinurenina em um novo modelo animal de aterosclerose associada ao HIV

Abstract

Introduction: A new mouse model of HIV-associated atherosclerosis (Tg26+/-ApoE-/-) exhibited increased plaque area compared to the ApoE-/- mouse, linked to elevated indoleamine 2,3-dioxygenase (IDO) activity. IDO catalyzes 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. Purpose: To investigate the effect of exercise training on atherogenesis and IDO activity in Tg26+/−ApoE−/− mice. Methods: Nine Tg26+/-ApoE-/- and 18 ApoE-/- 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 (5 times/wk at 60% maximum velocity). KYN, TRP, and circulating pro-inflammatory cytokines concentrations were measured using ELISA, and immune expression was assessed by flow cytometry. After euthanasia, the whole aorta was harvested, processed, and stained for en-face analysis. Results: Tg26+/-ApoE-/- mice showed approximately 40% larger atherosclerotic plaques than ApoE-/- mice (P = 0.01) and slightly higher neutrophil (P = 0.05) and monocyte expression (P = 0.06). Plaque formation was reduced by approximately 40% in exercised ApoE-/- mice (P = 0.04), but only by 12% in exercised Tg26+/-ApoE-/- mice (P = 0.85). The exercise training improved exercise capacity in both animal groups, as expressed by both the time to exhaustion and the distance achieved in the incremental test (P < 0.01). All groups gained body mass throughout the experiment. However, white adipose tissue gain was reduced in the exercised Tg26+/−/ApoE−/− (P = 0.003) and ApoE−/− (P = 0.01) mice compared to their respective control groups. Additionally, exercised Tg26+/-ApoE-/- showed higher IDO activity than exercised ApoE-/- (58.57 ± 6.88 vs. -4.62 ± 17.20 %, P = 0.01), which correlated positively with plaque area (R = 0.99, P = 0.02). No differences were detected in circulating pro-inflammatory cytokines levels. Conclusion: Unlike ApoE−/− mice, moderate-intensity aerobic training did not reduce plaque area in HIV-associated atherosclerosis mice. Moreover, exercise training appeared to increase inflammation in Tg26+/-ApoE-/-, as indicated by elevated IDO activity