Exercise-induced Effects On Atherogenesis And Tryptophan Catabolism Via The Kynurenine Pathway In Hiv-associated Atherosclerosis

A novel mouse model of HIV-associated atherosclerosis (Tg26+/-ApoE-/-) showed increased plaque area compared to the ApoE-/- mouse. This response was accompanied by an increased tryptophan (TRP) catabolism via the kynurenine (KYN) pathway, evidenced by the indoleamine 2,3-dioxygenase (IDO) activity (TRP/KYN ratio). This metabolic shift may have implications for immune responses and inflammation, particularly in the context of HIV-infection. Non-pharmacological therapeutic strategies to mitigate atherosclerosis by reducing chronic inflammation, such as exercise training, need exploration. PURPOSE: To investigate the effect of exercise training on atherogenesis and TRP catabolism via the KYN pathway in Tg26+/−ApoE−/− mice. METHODS: Eight-week-old Tg26+/-ApoE-/- (n = 17) and ApoE-/- (n = 20) mice were fed an atherogenic diet and randomized into sedentary (SED) or exercised (EXE) groups. The EXE groups underwent an 8-week treadmill protocol at moderate intensity (5 times a week at 60% maximum velocity). Blood was collected by tail bleeding at baseline and after exercise training. KYN and TRP concentrations were measured through competitive ELISA. After euthanasia, the whole aorta was harvested, processed, and stained for en-face analysis. Plaque area and IDO activity (KYN/TRP ratio) were compared using a two-way ANOVA with Tukey post-hoc for multiple comparisons. RESULTS: The plaque area was smaller in EXE than SED ApoE-/- (3.37 ± 0.30 vs. 5.71 ± 0.47 %, p = 0.03), but similar between EXE and SED Tg26+/-ApoE-/- (EXE: 7.69 ± 1.23 vs. SED: 9.81 ± 1.31 %, p = 0.30). Changes from baseline (%) for the IDO activity at 8 weeks were higher in EXE versus SED Tg26+/-ApoE-/- (61.31 ± 9.04 vs. 5.25 ± 6.31 %, p = 0.003), while no difference was found between EXE and SED ApoE-/- (EXE: 1.23 ± 10.64 vs. SED: -30.36 ± 10.05 %, p = 0.20). CONCLUSION: Unlike the ApoE knockout mice, aerobic moderate-intensity exercise training did not reduce the plaque area in HIV-associated atherosclerosis mice. Moreover, exercise training appeared to increase inflammation in Tg26+/-ApoE-/-, as measured by IDO activity. HIV infection may increase susceptibility to overexertion. The dose-response relationship between aerobic exercise training and markers of atherosclerosis and inflammation should be further investigated in Tg26+/−ApoE−/− mice. CNPq and FAPERJ grant (E-26/200.132/2023)