The Maladaptive Effects of HIV Protease Inhibitors (Lopinavir/Ritonavir) on the Rat Heart

Kathleen M.S.E. Reyskens, Tarryn Lee Fisher, Jonathan C. Schisler, Wendi G. O'Connor, Arlin B. Rogers, Monte Willis, Cynthia Planesse, Philippe Rondeau, Emmanuel Bourdon, M. Faadiel Essop

Research output: Contribution to journalArticle

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Abstract

Although antiretroviral treatment decreases HIV-AIDS morbidity/mortality, long-term effects include onset of insulin resistance and cardiovascular diseases. Increased oxidative stress and dysregulation of the ubiquitin-proteasome system (UPS) are implicated in protease-inhibitor (PI)-mediated cardio-metabolic pathophysiology. We hypothesized that PI treatment (Lopinavir/Ritonavir) elevates myocardial oxidative stress and concomitantly inhibits the 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. Subsequently, we evaluated metabolic parameters and heart function (ex vivo Langendorff perfusions) at baseline and following ischemia-reperfusion. PI-treated rats exhibited weight gain, increased serum LDL-cholesterol, higher tissue triglycerides (heart, liver), but no evidence of insulin resistance. It also upregulated hepatic gene expression of 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 UPS, increased SOD activity and unaltered superoxide levels, and elevated peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) peptide levels. Perfusion data revealed contractile dysfunction at baseline and following ischemia-reperfusion, while post-ischemic hearts exhibited decreased ATPase specific activity vs. matched controls. Early changes initiated by PI treatment resemble the metabolic syndrome and reflect a pre-atherogenic profile. Moreover, the effects of PIs on cardiac contractile function may in part be triggered by impaired UPS activity together with strain on the mitochondrial energetic system. Our study alerts to cardio-metabolic side effects of PI treatment and raises the question of the most appropriate co-therapies for patients on chronic antiretroviral treatment.

Original languageEnglish (US)
Article numbere73347
JournalPLoS ONE
Volume8
Issue number9
DOIs
StatePublished - Sep 30 2013
Externally publishedYes

Fingerprint

Lopinavir
HIV Protease Inhibitors
Ritonavir
proteinase inhibitors
Protease Inhibitors
Rats
heart
proteasome endopeptidase complex
Proteasome Endopeptidase Complex
ubiquitin
Ubiquitin
rats
Oxidative stress
ischemia
insulin resistance
Reperfusion
Insulin Resistance
Oxidative Stress
oxidative stress
Therapeutics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Reyskens, K. M. S. E., Fisher, T. L., Schisler, J. C., O'Connor, W. G., Rogers, A. B., Willis, M., ... Essop, M. F. (2013). The Maladaptive Effects of HIV Protease Inhibitors (Lopinavir/Ritonavir) on the Rat Heart. PLoS ONE, 8(9), [e73347]. https://doi.org/10.1371/journal.pone.0073347

The Maladaptive Effects of HIV Protease Inhibitors (Lopinavir/Ritonavir) on the Rat Heart. / Reyskens, Kathleen M.S.E.; Fisher, Tarryn Lee; Schisler, Jonathan C.; O'Connor, Wendi G.; Rogers, Arlin B.; Willis, Monte; Planesse, Cynthia; Rondeau, Philippe; Bourdon, Emmanuel; Essop, M. Faadiel.

In: PLoS ONE, Vol. 8, No. 9, e73347, 30.09.2013.

Research output: Contribution to journalArticle

Reyskens, KMSE, Fisher, TL, Schisler, JC, O'Connor, WG, Rogers, AB, Willis, M, Planesse, C, Rondeau, P, Bourdon, E & Essop, MF 2013, 'The Maladaptive Effects of HIV Protease Inhibitors (Lopinavir/Ritonavir) on the Rat Heart', PLoS ONE, vol. 8, no. 9, e73347. https://doi.org/10.1371/journal.pone.0073347
Reyskens, Kathleen M.S.E. ; Fisher, Tarryn Lee ; Schisler, Jonathan C. ; O'Connor, Wendi G. ; Rogers, Arlin B. ; Willis, Monte ; Planesse, Cynthia ; Rondeau, Philippe ; Bourdon, Emmanuel ; Essop, M. Faadiel. / The Maladaptive Effects of HIV Protease Inhibitors (Lopinavir/Ritonavir) on the Rat Heart. In: PLoS ONE. 2013 ; Vol. 8, No. 9.
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