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

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.

N-Acetylcysteine Reverses Antiretroviral-Mediated Microglial Activation by Attenuating Autophagy-Lysosomal Dysfunction

“…The rationale for using the antiretroviral cocktail in this study is based on the fact that this regimen is not only shown to be effective in inhibiting virus replication in the clinical setting ( 25 , 28 – 30 ) but also have been efficacious in the SIV–macaque model ( 26 , 27 ), as well as the humanized mouse model of HIV-1 infection ( 32 ). According to the US Food and Drug Administration, due to the increased metabolic rates exhibited by rats, the recommended equivalent drug dose should be ~6 times higher than the human dose ( 33 , 34 ). We have followed guidelines for maximum injection volume by species and site location ( 33 ).…”

Silver Nanoparticles Conjugate Attenuates Highly Active Antiretroviral Therapy-Induced Hippocampal Nissl Substance and Cognitive Deficits in Diabetic Rats

“…Group A: nondiabetic control+vehicle (0.5 mL/100 g) Group B: nondiabetic+HAART (98.2 mg/kg b.w oral) Group C: nondiabetic+HAART-AgNPs (24.5 mg/kg b.w i. p) Group D: diabetic control+vehicle (0.5 mL/100 g) Group E: diabetic+HAART (98.2 mg/kg b.w oral) Group F: diabetic+HAART-AgNPs (24.5 mg/kg b.w i. p) Everson et al [33].…”

Tenofovir-silver nanoparticles conjugate ameliorates neurocognitive disorders and protects ultrastructural and cytoarchitectonic properties of the prefrontal cortex in diabetic rats

“…Groups 4-6 were diabetic rats designated as diabetic control (DC) administered 0.5 ml/100g distilled water p.o., diabetic + Tenofovir (DT) administered 26.8 mg/kg/bw TDF p.o., and diabetic + silver-nanoparticles + tenofovir (DST) administered 6.7 mg/kg TDF-AgNPs i.p. The drug dosage was determined according to Everson et al [33] Induction of Type II Diabetes Mellitus in rats Type 2 diabetes mellitus was induced using the fructose-Streptozotocin (STZ) rat model as described by [34]. Groups 4-6 rats received 10% fructose solution ad libitum for two weeks.…”