The effects of HIV protease inhibitors on the rat heart

Symington, Burger (2016-03)

Thesis (MSc)--Stellenbosch University, 2016.

Thesis

ENGLISH ABSTRACT: Since the early 1990’s HIV/AIDS emerged as a global health pandemic, with sub-Saharan Africa the hardest hit. While the successful roll-out of antiretroviral (ARV) therapy provided significant relief to HIV-positive individuals, such treatment can also elicit damaging side-effects. Here especially HIV protease inhibitors (PIs) are implicated in the onset of cardiometabolic complications such as type-2 diabetes and acute myocardial infarction. As the underlying mechanisms driving PI-mediated sideeffects remain unclear, this study set out to investigate this intriguing question by employing a rat model of chronic PI treatment (6 months). In addition, various co-treatments (Resveratrol, Aspirin, Vitamin C) were evaluated to ascertain whether such a therapeutic strategy may blunt PI-induced side-effects. Body weights and weight gains, blood metabolite levels, echocardiography and cardiac mitochondrial respiration were assessed. Our data reveal that after 2 months of PI treatment there were no significant changes for the various parameters evaluated in this study. However, after 4 months Vitamin C co-treatment ameliorated the PI-induced decrease in body weight, while it also blunted the PI-mediated inhibition of mitochondrial respiration. Aspirin co-treatment also improved mitochondrial respiration while this effect was not observed with Resveratrol. After 6 months of PI treatment all interventions prevented the PI-induced increase in body weights, while Aspirin and Vitamin C prevented the PI-induced increase in heart weight. At the later time point mitochondrial respiration was, unlike at the 4 month time point, not affected by PI treatment. However, Resveratrol co-treatment significantly increased mitochondrial respiration. This study demonstrates that early PI-mediated perturbations include alterations in body weights and inhibition of mitochondrial respiration. However, no significant changes were found for heart function or blood metabolites. Our findings show that the co-treatments triggered beneficial outcomes by reversing weight changes and enhancing mitochondrial respiratory function. As the co-treatments are already well-known and approved therapeutic agents, we are of the opinion that this study provides significant impetus to test such compounds to establish whether our basic findings can be successfully translated into the clinical setting to eventually improve the overall well-being of HIVpositive patients.

AFRIKAANSE OPSOMMING: Sedert die vroeë 1990’s het HIV/VIGS ‘n globale pandemie geword, met Sub-Sahara Afrika veral ernstig getref. Alhoewel die suksesvolle uitreiking van antiretrovirale (ARV) terapie al talle HIVpositiewe individue gehelp het, kan hierdie middels skadelike newe-effekte veroorsaak. Meer spesifiek, HIV protease inhibitore (PIs) word geïmpliseer in die ontwikkeling van kardio metaboliese komplikasies soos tipe-2 diabetes en miokardiale infarksies. Aangesien die meganismes van die komplikasies nie bekend is nie, is hierdie studie gemik daarop om hierdie meganismes te ondersoek. Dit is uitgevoer deur n rot-model van kroniese PI behandeling (6 maande). Addisioneel is verskeie intervensies (Resveratrol, Aspirien, Vitamien C) getoets om te ondersoek of sulke terapeutiese middels die PI-geïndiseerde newe-effekte kan beveg. Liggaamsgewig en gewigsvermeerdering, bloed metaboliet vlakke, eggokardiografie en kardiale mitochondriale respirasie is geassesseer. Ons data wys na 2 maande van PI behandeling geen beduidende verskille in die getoetste parameters nie. Na 4 maande het mede-behandeling van Vitamien C egter die PI-geïnduseerde gewigsverlies voorkom, sowel as die PI-geïnduseerde inhibisie van mitochondriale respirasie. Aspirien mede-behandeling het ook mitochondriale respirasie verbeter, maar hierdie effek is nie waargeneem met Resveratrol mede-behandeling nie. Na 6 maande van PI behandeling het al die intervensies daarin geslaag om die PI geïnduseerde gewigsvermeerdering te voorkom. Aspirien en Vitamien C was ook suksesvol om die PI geïnduseerde gewigsvermeerdering te voorkom. Aspirien en Vitamien C het ook suksesvol die PI geïnduseerde hartgewig vermeerdering voorkom. Na 6 maande was mitochondriale respirasie nie deur PI behandeling geaffekteer nie. Resveratrol mede-behandeling het wel mitochondriale respirasie beduidend verhoog na 6 maande van behandeling. Hierdie studie demonstreer dat veranderinge in liggaamsgewig en mitochondriale respirasie deel uitmaak van vroeë PI geïnduseerde newe-effekte. Daar is egter geen veranderinge in hart funksie of bloed metaboliete waargeneem nie. Ons bevindings toon dat die mede-behandelinge voordelige resultate gelewer het deur liggaamsgewig veranderinge om te keer en mitochondriale respirasie te verbeter. Aangesien hierdie mede-behandelinge reeds welbekend en goedgekeurde terapeutiese middels is, glo ons dat hierdie studie goeie rede lewer om meer toetse op hierdie middels te doen. Dit kan gedoen word om vas te stel of ons basiese bevindings getransleer kan word in die kliniese omgewing om eventueel die gesondheid van HIV-pasiënte te verbeter.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/98316
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