Treatment with a fixed dose combination antiretroviral therapy drug containing tenofovir, emtricitabine and efavirenz is associated with cardioprotection in high calorie diet-induced obese rats

PLoS One. 2018 Dec 5;13(12):e0208537. doi: 10.1371/journal.pone.0208537. eCollection 2018.

Abstract

HIV-infection, certain antiretroviral drug classes, especially protease inhibitors (PI), and obesity are associated with increased ischaemic heart disease (IHD) risk. However, the effect of PI-free fixed dose combination (FDC) antiretroviral therapy (ART) on hearts exposed to ischaemia-reperfusion injury (I/R) is unknown, particularly in obesity. This is becoming relevant as World Health Organisation guidelines recommend a FDC ART containing (non-) nucleoside reverse transcriptase inhibitors (tenofovir (TDF), emtricitabine (FTC) and efavirenz (EFV)) as first-line HIV treatment. Additionally, obesity rates are rising in HIV-infected populations, not only in ART-experienced individuals, but also at the time of ART initiation, which may further increase the risk of IHD. Therefore, we investigated the effects of PI-free FDC ART in myocardial I/R-exposed hearts from obese rats. Obesity was induced in male wistar rats via a 16-week high calorie diet. At week 10, treatment with a FDC ART drug containing TDF/FTC/EFV was initiated. Biometric and metabolic parameters, as well as myocardial functional recovery and infract size (IS), and myocardial signalling proteins following I/R were assessed after 16 weeks. Obese rats presented with increased body and intraperitoneal fat mass, elevated triglyceride and TBARS levels, whilst the hearts responded to I/R with impaired functional performance and increased IS. The FDC ART treatment did not alter biometric and metabolic parameters in obese rats. In a novel finding, ART protected obese hearts against I/R as shown by improved functional performance and smaller IS vs. untreated obese hearts. Cardioprotection was underscored by increased myocardial phosphorylated endothelial nitric oxide synthase (eNOS) and reduced AMP-kinase levels. In conclusion, these results demonstrate for the first time, that 6-weeks treatment of obese rats with a FDC ART drug specifically containing TDF/FTC/EFV conferred cardioprotection against I/R. The FDC ART-induced cardioprotection was seemingly unrelated to metabolic changes, but rather due to direct cardiac mechanisms including the up-regulation of myocardial eNOS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Alkynes
  • Animals
  • Anti-Retroviral Agents / pharmacology
  • Anti-Retroviral Agents / therapeutic use*
  • Benzoxazines / pharmacology
  • Benzoxazines / therapeutic use*
  • Cyclopropanes
  • Diet, High-Fat*
  • Drug Therapy, Combination
  • Emtricitabine / pharmacology
  • Emtricitabine / therapeutic use*
  • Heart / drug effects
  • Male
  • Myocardium / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Obesity / pathology*
  • Oxidative Stress / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Wistar
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / prevention & control*
  • Reperfusion Injury / veterinary
  • Tenofovir / pharmacology
  • Tenofovir / therapeutic use*

Substances

  • Alkynes
  • Anti-Retroviral Agents
  • Benzoxazines
  • Cyclopropanes
  • Tenofovir
  • Nitric Oxide Synthase Type III
  • Proto-Oncogene Proteins c-akt
  • AMP-Activated Protein Kinases
  • Emtricitabine
  • efavirenz

Grants and funding

This study was funded by the South African National Research Foundation (Acquisition: HS and AG; http://www.nrf.ac.za/; grant numbers: CSUR13082330472 and TTK13061118934), Harry Crossley Foundation (Acquisition: AG; https://educationinnovations.org/funder/harry-crossley-foundation) and the South African Department of Science and Technology (Acquisition: HS; www.dst.gov.za; Grant number: DST/CON 0077/2014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.