Liver transcriptomic changes associated with ritonavir-induced hyperlipidemia in sensitive and resistant strains of rats

Yang, Yi; Dahly-Vernon, Annette J.; Blomme, Eric A.G.; Lai-Zhang, Jie; Kempf, Dale J.; Marsh, Kennan C.; Harrington, Yvette A.; Nye, Steven H.; Evans, Darin L.; Roman, Richard J.; Jacob, Howard J.; Waring, Jeffrey F.

doi:10.1016/j.tvjl.2010.04.017

Cited by 6 publications

(8 citation statements)

References 27 publications

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“…Rats have much higher drug metabolic rates compared with humans and require at least 6-fold higher dose levels to achieve clinically comparable circulating HAART levels. In the present study, the selected dose of RTV did cause hyperlipidemia in LBNF1 rats, which are one of the few strains reported to exhibit this PI-induced sensitivity observed in humans (50). RTV induced sustained elevations in plasma cholesterol and TG levels throughout the entire 8-wk treatment period.…”

Section: Discussionsupporting

confidence: 46%

“…Sprague-Dawley (SD) rats were found to be less sensitive to PI-induced lipogenesis than LBNF1 rats. Using microarray assessment, Yang et al (50) reported that a subset of four genes important to lipid and carbohydrate metabolism were differentially regulated by RTV in SD and LBNF1 rats after only 5 days of RTV treatment. Using a RT quantitative-PCR approach, we assessed the effects of RTV treatment at a comparable dose (75 mg·day Ϫ1 ·kg Ϫ1 ) on this subset of genes.…”

Section: Rtv Treatment and Mg Diets Effect On Weight Gain (5 Wk) And mentioning

confidence: 99%

“…Recently, we reported that Mg supplementation provided effective antiperoxidative effects against AZT-induced systemic oxidative stress and cardiac inflammation in normomagnesemic rats (31). The Lewis ϫ Brown Norway F1 hybrid rat (LBNF1) was recently shown to be very sensitive to RTVinduced hyperlipidemia in a manner similar to that exhibited by humans (50). In the current study, we used this rat model to examine the effects of dietary Mg supplementation on RTVmediated hyperlipidemia, and changes in hepatic lipid metab-olism genes.…”

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Mg supplementation attenuates ritonavir-induced hyperlipidemia, oxidative stress, and cardiac dysfunction in rats

Mak

Kramer

Chen

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Mak IT, Kramer JH, Chen X, Chmielinska JJ, Spurney CF, Weglicki WB. Mg supplementation attenuates ritonavir-induced hyperlipidemia, oxidative stress, and cardiac dysfunction in rats. Am J Physiol Regul Integr Comp Physiol 305: R1102-R1111, 2013. First published September 18, 2013 doi:10.1152/ajpregu.00268.2013.-Use of protease inhibitors (PI) in HIV patients is associated with hyperlipidemia and increased risk of coronary heart disease. Chronic systemic and cardiac effects of ritonavir (RTV), a universal PI booster, and Mg supplementation were examined. RTV was administered (75 mg·kg Ϫ1 ·day Ϫ1 po) to LewisϫBrown-Norway hybrid (LBNF1) rats for up to 8 wk; significant increases in plasma triglyceride and cholesterol occurred from 8 days to 8 wk. At 5 wk, the expression of selected hepatic genes (CYP7A1, CITED2, G6PC, and ME-1), which are key to lipid catabolism/synthesis, were altered toward lipogenesis. Dietary Mg supplementation (six-fold higher) completely reversed the altered expression of these genes and attenuated both hypertriglyceridemia and hypercholesterolemia. Neutrophils isolated from the RTV-treated rats displayed a three-fold higher basal and a twofold higher stimulated superoxide production; plasma isoprostane and red blood cell (RBC) GSSG levels were elevated twoto three-fold. All oxidative indices were normalized by Mg supplementation. After 5 wk, RTV caused significant decreases in cardiac left ventricular (LV) shortening fraction and LV ejection fraction; mitral valve early/late atrial ventricular filling (E/A) ratio was reduced accompanied by LV posterior wall thinning. Immunohistochemical staining revealed significant white blood cell (WBC) infiltration (5 wk) and prominent fibrosis (8 wk) in the RTV hearts. Mg supplementation attenuated RTV-induced declines in systolic and diastolic (improved mitral valve E/A ratio) function (Ͼ70%), lessened LV posterior wall thinning (by 75%), and substantially decreased the pathological markers. The known clinical hyperlipidemia effects of RTV can be mimicked in the LBNF1 rats; in association, systemic oxidative stress and progressive cardiac dysfunction occurred. Remarkably, Mg supplementation alone suppressed RTV-mediated hyperlipidemia, oxidative stress, and cardiac dysfunction.HIV-1 protease inhibitor ritonavir; hepatic metabolic gene regulation; hyperlipidemia; oxidative stress; cardiac dysfunction; dietary Mg supplementation ACCORDING TO A RECENT REPORT (47), there are 34 million people worldwide infected with HIV-1, and of these, 1.3 million are in the United States (7). Nucleoside/nucleotide analogs, with Zidovudine (AZT) as the prototype compound, were first introduced in the late 1980s and continue to play a significant role in HIV therapy (13). With the introduction of protein inhibitors (PIs) in the mid 1990s, HIV-1 replication in the patients was shown to be dramatically reduced, and currently, to the extent that HIV-1 infection has become a more manageable disease (20,23). However, along with the chronic use of PIs, significant metabolic si...

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Section: Discussionsupporting

confidence: 46%

Section: Rtv Treatment and Mg Diets Effect On Weight Gain (5 Wk) And mentioning

confidence: 99%

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confidence: 99%

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Mg supplementation attenuates ritonavir-induced hyperlipidemia, oxidative stress, and cardiac dysfunction in rats

Mak

Kramer

Chen

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The drug cocktail composed of AZT (100 mg kg −1 day −1 ), ritonavir (20 mg kg −1 day −1 ), and saquinavir (25 mg kg −1 day −1 ) was administered twice daily for 7 days by continuous intravenous injection. Each drug dose was based on previously published studies in rodents (Shibata et al 2002; Huisman et al 2003; Manda et al 2010; Pistell et al 2010; Waring et al 2010; Yang et al 2010; du Plooy et al 2011; Fontes et al 2011; Lledo-Garcia et al 2011; Wagner et al 2011; Mak et al 2013; Reyskens and Essop 2013a, b; Reyskens et al 2013). The catheters were flushed with 0.3 ml heparin (50 IU/ml) in PBS until the end of treatments.…”

Section: Methodsmentioning

confidence: 99%

Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system

et al. 2014

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HIV-associated neurocognitive disorder (HAND), characterized by a wide spectrum of behavioral, cognitive, and motor dysfunctions, continues to affect approximately 50 % of HIV(+) patients despite the success of combination antiretroviral drug therapy (cART) in the periphery. Of note, potential toxicity of antiretroviral drugs in the central nervous system (CNS) remains remarkably underexplored and may contribute to the persistence of HAND in the cART era. Previous studies have shown antiretrovirals (ARVs) to be neurotoxic in the peripheral nervous system in vivo and in peripheral neurons in vitro. Alterations in lipid and protein metabolism, mitochondrial damage, and oxidative stress all play a role in peripheral ARV neurotoxicity. We hypothesized that ARVs also induce cellular stresses in the CNS, ultimately leading to neuronal damage and contributing to the changing clinical and pathological picture seen in HIV-positive patients in the cART era. In this report, we show that ARVs are neurotoxic in the CNS in both pigtail macaques and rats in vivo. Furthermore, in vitro, ARVs lead to accumulation of reactive oxygen species (ROS), and ultimately induction of neuronal damage and death. Whereas ARVs alone caused some activation of the endogenous antioxidant response in vitro, augmentation of this response by a fumaric acid ester, monomethyl fumarate (MMF), blocked ARV-induced ROS generation, and neuronal damage/death. These findings implicate oxidative stress as a contributor to the underlying mechanisms of ARV-induced neurotoxicity and will provide an access point for adjunctive therapies to complement ARV therapy and reduce neurotoxicity in this patient population.

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“…To examine the RTV effects on eNOS status in vivo , we chose to use the LBN-F1 hybrid rats which were reported to be sensitive to RTV-mediated metabolic side effects [42]. The dose of RTV used in the current study was 5–11 fold higher than the recommended human dose.…”

Section: Discussionmentioning

confidence: 99%

Mg supplementation protects against ritonavir-mediated endothelial oxidative stress and hepatic eNOS downregulation

Chen

Mak

2014

Free Radical Biology and Medicine

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Ritonavir (RTV), a prototypical protease inhibitor currently used as a key component for anti-HIV therapy, is known for its endothelial and hepatic toxicity. The effects of RTV and Mg-supplementation on cultured bovine endothelial cells (EC) and rat hepatic endothelial nitric oxide synthase (eNOS) status were investigated. RTV dose-dependently (5–30µM) decreased EC viability after 48hrs; high Mg (2 mM) significantly attenuated the lost viability. ECs incubated with 15 µM RTV for 6 to 24 hrs. resulted in 2–4-fold elevation of oxidized glutathione and a 25% loss of total glutathione. At 24 hrs., EC superoxide production due to RTV was detected by dihydroethidium staining, and increased 41% when quantified by flow cytometry; both altered glutathione status and superoxide levels were substantially reversed by 2 mM Mg. RTV reduced eNOS mRNA (−25% at 24 hrs.), and led to decreased eNOS dimer/monomer ratios; nitric oxide (NO)-derived products decreased 40%; both changes were attenuated by Mg-supplementation. In male LewXBrown-Norway rats, RTV administration (75 mg/kg/day, 5 weeks) resulted in an 85% increase in plasma 8-isoprostane, a 30% decrease of hepatic eNOS mRNA; concomitantly, eNOS protein decreased 72%, whereas plasma nitrite level was reduced 49%. Dietary Mg-supplementation (6-fold higher than control) prevented the eNOS mRNA decrease along with lowering 8-isoprostane, and restored the eNOS protein and plasma nitrite levels comparable to controls. Conclusion Mg attenuates RTV-mediated EC oxidative eNOS dysfunction, and down-regulation of hepatic eNOS expression; we suggest that Mg can serve as a beneficial adjunct therapeutic against RTV-mediated eNOS toxicity.

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Liver transcriptomic changes associated with ritonavir-induced hyperlipidemia in sensitive and resistant strains of rats

Cited by 6 publications

References 27 publications

Mg supplementation attenuates ritonavir-induced hyperlipidemia, oxidative stress, and cardiac dysfunction in rats

Mg supplementation attenuates ritonavir-induced hyperlipidemia, oxidative stress, and cardiac dysfunction in rats

Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system

Mg supplementation protects against ritonavir-mediated endothelial oxidative stress and hepatic eNOS downregulation

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