Investigating the cardiovascular effects of antiretroviral drugs in a lean and high fat/sucrose diet rat model of obesity : an in vivo and ex vivo approach

[摘要] ENGLISH ABSTRACT: Introduction:An interaction exists between cardiovascular risk factors (e.g. obesity) and antiretroviral treatment (ART) in the pathogenesis of cardiovascular disease. While ART reverses HIV- related weight loss, studies investigating ART effects in the context of obesity are lacking.Objective:To investigate the effects of Odumine® (first-line fixed ART-drug combination) on several cardio-metabolic parameters in a high fat/sucrose diet (HFD) rat model of obesity.Methods:Groups: Lean, untreated (C/-ART); HFD, untreated (HFD/-ART); Lean, treated (C/+ART); HFD, treated (HF/+ART). Sample size: n = 28 - 34 / group; male Wistar rats. The HFD feeding programme followed for 16 weeks and ART treatment programme for the last 6 weeks of HFD feeding programme. The Endpoints measured included: Food and water consumption for the first 31 days during the drug treatment programme; Biometric measurements: Total body mass (TBM), intra-peritoneal (IP) fat mass, heart mass and liver mass; Blood and serum: Glucose, insulin, total cholesterol (TC), triglycerides (TGs); Thiobarbituric acid reactive substance (TBARS) and conjugated dienes (CD); Isolated heart perfusion: Functional recovery (Global ischaemia-reperfusion) and infarct sizes (Regional ishcaemia-reperfusion); Western blot (Pre- and post-ischaemia-reperfusion): Nitric oxide synthase (NOS) signalling (eNOS, PKB/Akt and AMPK), indicators of reactive oxygen species (ROS) (Nitrotyrosine and p22 phox) and an indicator of pro-inflammatory NF-κB signalling (IκBα) in heart tissue.Results:The HFD was validated by increases in TBM, IP fat mass and heart mass. The HFD was further validated by increased TG and TBARS levels (lipid peroxidation). Pre-ischaemia-reperfusion, the HFD was associated with reduced oxidative stress (nitrotyrosine and p22 phox) vs. C/-ART. Reduced oxidative stress was associated with increased activation of the pro-inflammatory NF-κB pathway. The HFD upregulated eNOS post-ischaemia- reperfusion, downregulated PKB/Akt and increased NF-κB activation. Lastly, the HFD was associated with reduced functional recovery vs. C/-ART and HF/+ART, and increased infarct size vs. C/-ART and HF/+ART.ART treatment did not affect the food and water consumption, was associated with reduced insulin levels vs. C/-ART and HF/+ART, increased TC levels vs. C/-ART and elevated levels of oxidative stress (increased TBARS) vs. C/-ART. Pre-ischaemia- reperfusion, ART improved oxidative stress in heart tissue (reduced p22 phox) vs. C/-ART and reduced inflammation (downregulated IκBα). Post-ichaemia-reperfusion, ART upregulated eNOS in the heart tissue, downregulated PKB/Akt and increased oxidative stress (nitrotyrosine) vs. C/-ART. ART per se did not affect functional recovery or infarct size.The HFD combined with ART increased liver mass vs. HF/-ART. Pre-ischaemia- reperfusion, HFD/+ART improved oxidative stress (decreased nitrotyrosine and p22 phox) vs. HF/-ART, but decreased NF-κB activation vs. HF/-ART. Post-ischaemia-reperfusion, ART combined with HFD upregulated eNOS, downregulated PKB/Akt and increased oxidative stress (p22 phox) vs. HF/-ART and C/+ART. Post-ischaemia-reperfusion, ART with HFD seemed to improved functional recovery vs. HF/-ART and ameliorated the increased infarct size vs. HF/-ART.Discussion and Conclusion:Our study demonstrates the detrimental effect of HFD/obesity on cardiovascular health. Interestingly, when combined with ART, cardiovascular function seem to be improved vs. HFD/-ART. ART alone, affected cardiovascular health to a lesser extent in our study vs. HF/-ART and HF/+ART, and did not affect functional recovery and infarct size vs. C/-ART at all.

[发布机构] Stellenbosch University