Combination Antiretroviral Therapy (cART) Altered Redox/Nitrosative genes, Enhanced Systemic Stress and Cardiac dysfunction in HIV-1 Transgenic (HIV-Tg) Rats: Effects of Magnesium Supplementation (Mg-Supp)

Mak, I. Tong; Kramer, Jay H.; ElZohary, Lama; Chmielinska, Joanna J.; Spurney, Chris F.; Weglicki, William B.

doi:10.1016/j.freeradbiomed.2017.10.175

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“…In contrast to our findings with the FDC ART drug, a previous study in rats exposed to mono-therapy with a single NRTI, showed increased myocardial NADPH-oxidase activity [69]. Increased myocardial nitrotyrosine levels were shown in NRTI / PI exposed transgenic HIV mice (18 weeks treatment), which was associated with cardiac dysfunction; however these observations may be the result of synergism between HIV-infection and ART, and the presence of a PI may have played a role [70]. After exposure to I/R, ART-treated control hearts showed a trend towards increased nitrosative stress (increased nitrotyrosine expression; p = 0.06); however, no changes were observed in the ART exposed obese group.…”

Section: Discussionmentioning

confidence: 97%

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

et al. 2018

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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.

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Section: Discussionmentioning

confidence: 97%