Cardio-Metabolic Effects of HIV Protease Inhibitors (Lopinavir/Ritonavir)

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.

Impact of Co-administered Lopinavir/Ritonavir and Sulfamethoxazole/Trimethoprim on Reproductive Indices of Male Albino Rats

“…Lopinavir/ritonavir tablets were crushed and dissolved in 1% ethanol while sulfamethoxazole/ trimethoprim tablets were crushed and suspended in water [27].…”

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…2013; Reyskens et al. 2013). Several studies also reported that some PIs are able to induce ER stress in different types of cells (e.g., macrophages, adipocytes, hepatocytes) and tissues (e.g., liver, intestine) (Zhou et al.…”

Lipid Management in Human Immunodeficiency Virus

“…PIs are the agents that produce the most adverse effects, but other categories, in particular nonnucleoside/nucleotide reverse transcriptase inhibitors may also influence lipids. 10,[22][23][24] Lipid Changes with Human Immunodeficiency Virus Infection and Antiretroviral Therapy Acute infection lowers low-density-lipoprotein cholesterol (LDL-C), 25 but levels may return to baseline after virologic suppression with ART. 26,27 Chronically, there is often a pattern of low HDL and elevated triglycerides (TG) that results from the metabolic abnormalities (insulin resistance, central adiposity, low HDL, and high TG) clustered in these patients 28,29 and often worsened by specific antiretrovirals, many of which are now less commonly prescribed.…”