HIV protease inhibitors and onset of cardiovascular diseases: A central role for oxidative stress and dysregulation of the ubiquitin–proteasome system

Abstract

The successful roll-out of highly active antiretroviral therapy (HAART) has extended life expectancy and enhanced the overall well-being of HIV-positive individuals. There are, however, increased concerns regarding HAART-mediated metabolic derangements and its potential risk for cardiovascular diseases (CVD) in the long-term. Here certain classes of antiretroviral drugs such as the HIV protease inhibitors (PIs) are strongly implicated in this process. This article largely focuses on the direct PI-linked development of cardio-metabolic complications, and reviews the inter-linked roles of oxidative stress and the ubiquitin-proteasome system (UPS) as key mediators driving this process. It is proposed that PIs trigger reactive oxygen species (ROS) production that leads to serious downstream consequences such as cell death, impaired mitochondrial function, and UPS dysregulation. Moreover, we advocate that HIV PIs may also directly lower myocardial UPS function. The attenuation of cardiac UPS can initiate transcriptional changes that contribute to perturbed lipid metabolism, thereby fueling a pro-atherogenic milieu. It may also directly alter ionic channels and interfere with electrical signaling in the myocardium. Therefore HIV PI-induced ROS together with a dysfunctional UPS elicit detrimental effects on the cardiovascular system that will eventually result in the onset of heart diseases. Thus while HIV PIs substantially improve life expectancy and quality of life in HIV-positive patients, its longer-term side-effects on the cardiovascular system should lead to a) greater clinical awareness regarding its benefit-harm paradigm, and b) the development and evaluation of novel co-treatment strategies.

Relationship between plasma bilirubin level and oxidative stress markers in HIV‐infected patients on atazanavir‐ vs. efavirenz‐based antiretroviral therapy

“…Similarly, the use of PIs is associated with increased OS biomarkers. It has been proposed that PIs may increase ROS production which induces cell death, impaired mitochondrial function and ubiquitin‐proteasome system (UPS) dysregulation . In contrast, Hileman et al .…”

The ubiquitin–proteasome system and autophagy are defective in the taurine-deficient heart

“…Also, the mitochondrial matrix, which is subject to extensive quality control, contains AAA proteases that remove proteins damaged by ROS (Hammerling and Gustafsson 2014). Particularly noteworthy in the present study is the observation that mitoTEMPO treatment normalizes ubiquitinated protein content, suggesting that ROS inhibits protein degradation, a property of the UPS, but not that of the MAD pathway (Taylor and Rutter 2011;Voigt et al 2013;Reyskens and Essop 2014;Segref et al 2014). Together, the data suggest that taurine deficiency and mitochondrial oxidative stress are associated with a reduction in protein degradation accompanied by an elevation in the levels of ubiquitinated protein.…”

Resveratrol Co-Treatment Attenuates the Effects of HIV Protease Inhibitors on Rat Body Weight and Enhances Cardiac Mitochondrial Respiration

“…Moreover, HIV-positive children receiving ARVs exhibited relatively high incidences of mild ventricular dysfunction together with progressive increases in left ventricular weight [47]. In addition, we previously found that two months of PI treatment resulted in attenuated ex vivo heart function at baseline and in response to ischemia-reperfusion [48]. The exact mechanisms of such PI-induced structural and functional abnormalities are elusive, but hypertension, vascular inflammation, endothelial dysfunction, myocardial calcium handling and impaired protein recycling are all proposed as potential mediators [16,45].…”