Cardio-metabolic effects of HIV protease inhibitors (Lopinavir/Ritonavir)

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dc.contributor.authorReyskens, Kathleen M. S. E.
dc.contributor.authorFisher, Tarryn-Lee
dc.contributor.authorSchisler, Jonathan C.
dc.contributor.authorO'Connor, Wendi G.
dc.contributor.authorRogers, Arlin B.
dc.contributor.authorWillis, Monte S.
dc.contributor.authorPlanesse, Cynthia
dc.contributor.authorBoyer, Florence
dc.contributor.authorRondeau, Philippe
dc.contributor.authorBourdon, Emmanuel
dc.contributor.authorEssop, M. F.
dc.date.accessioned2014-02-13T14:23:39Z
dc.date.available2014-02-13T14:23:39Z
dc.date.issued2013-11
dc.descriptionPublication of this article was funded by the Stellenbosch University Open Access Fund.en_ZA
dc.descriptionThe original publication is available at http://www.plosone.org/en_ZA
dc.description.abstractAlthough 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 b 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.en_ZA
dc.description.sponsorshipStellenbosch Universityen_ZA
dc.description.versionPublishers' versionen_ZA
dc.format.extent11 p. : ill.
dc.identifier.citationReyskens, K. M. S. E. et al. 2013. Cardio-metabolic effects of HIV protease inhibitors (Lopinavir/Ritonavir). PLoS ONE, 8(9):e73347, doi:10.1371/journal.pone.0073347.en_ZA
dc.identifier.issn1932-6203 (print)
dc.identifier.issn1932-6203 (online)
dc.identifier.otherdoi:10.1371/journal.pone.0073347
dc.identifier.urihttp://hdl.handle.net/10019.1/86149
dc.language.isoen_ZAen_ZA
dc.publisherPLoSen_ZA
dc.rights.holderAuthors retain copyrighten_ZA
dc.subjectHIV protease inhibitorsen_ZA
dc.subjectAntiviral agentsen_ZA
dc.subjectLopinavir/Ritonaviren_ZA
dc.titleCardio-metabolic effects of HIV protease inhibitors (Lopinavir/Ritonavir)en_ZA
dc.typeArticleen_ZA
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