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Elevated indoleamine-2,3-dioxygenase enzyme activity in a novel mouse model of HIV-associated atherosclerosis
Alison C Kearns1, Stephani Velasquez1, Fengming Liu1,2
1Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA.
Insights
A new mouse model shows that increased indoleamine-2,3-dioxygenase (IDO) activity, measured by the kynurenine to tryptophan ratio (KTR), accelerates HIV-associated atherosclerosis. This finding aids understanding of HIV cardiovascular disease pathogenesis.
Area of Science:
- Immunology
- Cardiovascular Science
- Virology
Background:
- HIV and cardiovascular disease (CVD) pose significant health challenges for patients on combination antiretroviral therapy (cART).
- Understanding the pathogenesis of HIV-associated atherosclerosis is limited by the absence of suitable small animal models.
- Indoleamine-2,3-dioxygenase (IDO) activity, indicated by the kynurenine to tryptophan ratio (KTR), is a biomarker of inflammation linked to CVD risk in people living with HIV (PLWH).
Purpose of the Study:
- To develop and characterize a novel mouse model for studying HIV-associated atherosclerosis and its link to IDO activity.
- To investigate the role of IDO enzyme activity in the progression of atherosclerosis in the context of HIV infection.
- To explore the potential mechanisms, such as cytokine involvement, driving HIV-associated CVD.
Main Methods:
- Generation of a novel Tg26/ApoE mouse model for HIV atherosclerosis.
- Assessment of atherogenesis and IDO activity (serum KTR) over 8 weeks on a high-fat diet.
- Comparison of Tg26/ApoE mice with single transgenic Tg26 and ApoE mice, including measurement of serum cytokines like IL-6.
Main Results:
- The Tg26/ApoE mouse model exhibited accelerated atherosclerosis.
- Increasing KTR levels in Tg26/ApoE mice correlated with plaque progression.
- Elevated circulating IL-6 levels were associated with accelerated plaque formation, suggesting a potential mechanism.
Conclusions:
- The Tg26/ApoE mouse is a viable model for studying HIV-induced atherogenesis.
- This model facilitates research into the role of tryptophan catabolism in HIV atherosclerosis and CVD pathogenesis.
- Findings highlight the potential link between IDO activity, inflammation (IL-6), and cardiovascular complications in HIV.
Objective:
HIV atherosclerosis and cardiovascular disease (CVD) represent a significant human health burden in the era of combination antiretroviral therapy (cART). The pathogenesis of HIV atherosclerosis is still poorly understood, due, in part, to the lack of a suitable small animal model. Indoleamine-2,3-dioxygenase (IDO) enzyme activity is the first and rate-limiting step in tryptophan catabolism and is measured by the kynurenine to tryptophan ratio (KTR). The serum KTR is a biomarker of inflammation and has recently been implicated as an important risk factor for CVD in patients living with HIV (PLWH) who are virologically suppressed under cART. However, IDO activity in HIV-associated CVD has not been studied in mouse model before.
Design:
A novel mouse model of HIV atherosclerosis (Tg26/ApoE) was generated and examined for IDO activity and atherogenesis throughout 8 weeks on a high-fat diet. Tg26/ApoE mice were compared with Tg26 and ApoE single transgenic mice, before and during a high-fat diet.
Method:
Serum kynurenine, tryptophan and percentage of aortic plaque formation were measured. Additionally, levels of relevant cytokines were investigated in Tg26/ApoE and ApoE.
Results:
Tg26/ApoE developed an accelerated atherosclerosis with increasing levels of KTR that were associated with plaque progression. This accelerated plaque was potentially driven by elevated levels of circulating IL-6.
Conclusion:
These results indicate that Tg26/ApoE serve as a new mouse model for HIV-induced atherogenesis, and aid in understanding the role of tryptophan catabolism in the pathogenesis of HIV atherosclerosis/CVD.
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