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Elevated indoleamine 2,3-dioxygenase activity is associated with endothelial dysfunction in people living with HIV
Junyang Yang1, Rentian Cai2, Jingna Xun1
1Department of Infectious and Immune Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
Insights
Elevated indoleamine 2,3-dioxygenase (IDO) activity in people living with HIV (PLWH) is linked to endothelial dysfunction. Antiretroviral therapy (ART) reduced IDO activity and improved markers, suggesting ART can restore IDO levels in PLWH.
Area of Science:
- Cardiovascular Biology
- Immunology
- HIV Medicine
Background:
- Indoleamine 2,3-dioxygenase (IDO) plays a role in cardiovascular diseases (CVD) in people living with HIV (PLWH), but its precise function is debated.
- Elevated IDO activity is suspected to contribute to endothelial dysfunction in PLWH.
Purpose of the Study:
- To investigate the impact of elevated IDO activity on endothelial dysfunction in PLWH.
- To assess changes in IDO activity and endothelial markers following the initiation of antiretroviral therapy (ART).
Main Methods:
- A cohort of 38 ART-naïve PLWH was monitored for 36 months post-ART initiation.
- Plasma levels of IDO activity, endothelial dysfunction markers (sICAM-1, sVCAM-1), inflammatory factors, and lipids were measured.
- In vitro experiments exposed human aortic endothelial cells (HAEC) to interferon-γ, IDO/KMO inhibitors, and kynurenine.
Main Results:
- Pre-ART, PLWH showed higher plasma IDO activity, sICAM-1, and sVCAM-1 compared to healthy controls.
- ART initiation led to significant decreases in IDO activity and sICAM-1, with IDO returning to control levels.
- IDO activity positively correlated with sICAM-1 and sVCAM-1 before ART.
- In vitro, increased kynurenine and IDO expression in HAEC elevated reactive oxygen species (ROS) production with minimal endothelial dysfunction.
Conclusions:
- Long-term ART can restore elevated IDO activity in PLWH.
- IDO overexpression primarily influences ROS production in human aortic endothelial cells.
Abstract:
The precise role of indoleamine 2,3-dioxygenase (IDO) in cardiovascular diseases (CVD) among people living with HIV (PLWH) is still under debate, despite recognized links. This study aimed to investigate the impact of elevated IDO activity on endothelial dysfunction in PLWH. A total of 38 PLWH, who had not previously received anti-retroviral therapy (ART), were enrolled in the study. These participants were monitored for 36 months following the initiation of ART. Measurements including plasma levels of IDO activity, markers of endothelial dysfunction, inflammatory factors, and lipids. In vitro, human aortic endothelial cells (HAEC) were exposed to interferon-γ, an IDO inhibitor, a kynurenine 3-hydroxylase (KMO) inhibitor, as well as different concentrations of kynurenine. Pre-ART, PLWH demonstrated notably elevated plasma concentrations of soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1(sVCAM-1), and IDO activity in comparison to healthy controls. Post-ART, both IDO activity and sICAM-1 levels experienced a significant decrease, with IDO activity reaching levels comparable to those observed in healthy controls. Furthermore, a positive correlation was observed between IDO activity and sICAM-1 (p = 0.0002), as well as sVCAM-1 (p < 0.0001) before ART. In vitro, the augmentation of kynurenine concentration in the medium and the induction of IDO expression in HAEC resulted in increased production of reactive oxygen species (ROS), with minimal impact on endothelial dysfunction. From these findings, it can be concluded that long-term ART has the potential to restore the heightened IDO activity observed in PLWH. The overexpression of IDO primarily influences the expression of ROS in HAEC.
