Abstract
Although antiretroviral treatment decreases HIV-AIDS morbidity/mortality, long-term side effects may include the onset of insulin resistance and cardiovascular diseases. However, the underlying molecular mechanisms responsible for highly active antiretroviral therapy (HAART)-induced cardio-metabolic effects are poorly understood. In light of this, we hypothesized that HIV protease inhibitor (PI) treatment (Lopinavir/Ritonavir) elevates myocardial oxidative stress and concomitantly inhibits the ubiquitin proteasome system (UPS), thereby attenuating cardiac function. Lopinavir/Ritonavir was dissolved in 1% ethanol (vehicle) and injected into mini-osmotic pumps that were surgically implanted into Wistar rats for 8 weeks vs. vehicle and sham controls. We subsequently evaluated metabolic parameters, gene/protein markers and heart function (ex vivo Langendorff perfusions). PI-treated rats exhibited increased serum LDL-cholesterol, higher tissue triglycerides (heart, liver), but no evidence of insulin resistance. In parallel, there was upregulation of hepatic gene expression, i.e. acetyl-CoA carboxylase β and 3-hydroxy-3-methylglutaryl-CoA-reductase, key regulators of fatty acid oxidation and cholesterol synthesis, respectively. PI-treated hearts displayed impaired cardiac contractile function together with attenuated UPS activity. However, there was no significant remodeling of hearts exposed to PIs, i.e. lack of ultrastructural changes, fibrosis, cardiac hypertrophic response, and oxidative stress. Western blot analysis of PI-treated hearts revealed that perturbed calcium handling may contribute to the PI-mediated contractile dysfunction. Here chronic PI administration led to elevated myocardial calcineurin, nuclear factor of activated T-cells 3 (NFAT3), connexin 43, and phosphorylated phospholamban, together with decreased calmodulin expression levels. This study demonstrates that early changes triggered by PI treatment include increased serum LDL-cholesterol levels together with attenuated cardiac function. Furthermore, PI exposure inhibits the myocardial UPS and leads to elevated calcineurin and connexin 43 expression that may be associated with the future onset of cardiac contractile dysfunction.
Highlights
The human immunodeficiency virus (HIV) has infected over 40 million individuals over the last decade, with more than 5 million residing in sub-Saharan Africa [1,2]
highly active antiretroviral therapy (HAART) markedly improves the quality of life and prognosis of HIV-infected individuals, it elicits cardiometabolic side effects in the long-term
Since molecular mechanisms underlying this process are poorly understood, we evaluated early cardio-metabolic changes in a rat model of protease inhibitor (PI) treatment
Summary
The human immunodeficiency virus (HIV) has infected over 40 million individuals over the last decade, with more than 5 million residing in sub-Saharan Africa [1,2]. Protease inhibitors (PIs) form an integral part of HAART and side-effects include development of dyslipidemia, i.e. greater production of plasma triglycerides and lipids together with an adverse cholesterol profile [6,7,8]. Together such derangements elicit inflammation, stress the myocardium (9), and may potentially predict the onset of insulin resistance (IR) [10,11] and cardiac dysfunction (11). PIs are linked to increased risk for myocardial infarction [13] and cardiovascular abnormalities [14,15], with many changes resembling coronary artery disease [16]. PI-treated HIVinfected individuals exhibit elevated reactive oxygen species (ROS) production [18,19,20] that may trigger the activation of detrimental signaling and cell death pathways [21]
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