Impact of Darunavir, Atazanavir and Lopinavir Boosted with Ritonavir on Cultured Human Endothelial Cells: Beneficial Effect of Pravastatin

Auclair, Martine; Afonso, Pauline; Capel, Émilie; Caron-Debarle, Martine; Capeau, Jacqueline

doi:10.3851/imp2752

Cited by 35 publications

(47 citation statements)

References 57 publications

(79 reference statements)

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“…Treatment of endothelial cells with RTV, LPV, or ATV stimulates the expression of ICAM-1 and increases the adhesion of monocytes to endothelial cell monolayers. These findings are in-line with previous work showing that PIs elevate adhesion receptor expression, the secretion of inflammatory cytokines, and monocyte adhesion in HAEC or human coronary endothelial cells [65,66]. Given the central role that inflammation plays in the initiation and progression of atherosclerosis, the inflammatory responses evoked by PIs may contribute to the atherogenic potential of these drugs.…”

Section: Discussionsupporting

confidence: 90%

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Heme oxygenase-1-derived bilirubin counteracts HIV protease inhibitor-mediated endothelial cell dysfunction

Liu

Durante

Peyton

et al. 2016

Free Radical Biology and Medicine

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The use of HIV protease inhibitors (PIs) has extended the duration and quality of life for HIV-positive individuals. However there is increasing concern that this antiviral therapy may promote premature cardiovascular disease by impairing endothelial cell (EC) function. In the present study, we investigated the effect of HIV PIs on EC function and determined if the enzyme heme oxygenase (HO-1) influences the biological action of these drugs. We found that three distinct PIs, including ritonavir, atazanavir, and lopinavir, stimulated the expression of HO-1 protein and mRNA. The induction of HO-1 was associated with an increase in NF-E2-related factor-2 (Nrf2) activity and reactive oxygen species (ROS). PIs also stimulated HO-1 promoter activity and this was prevented by mutating the antioxidant responsive element or by overexpressing dominant-negative Nrf2. In addition, the PI-mediated induction of HO-1 was abolished by N-acetyl-L-cysteine and rotenone. Furthermore, PIs blocked EC proliferation and migration and stimulated the expression of intercellular adhesion molecule-1 and the adhesion of monocytes on ECs. Inhibition of HO-1 activity or expression potentiated the anti-proliferative and inflammatory actions of PIs which was reversed by bilirubin but not carbon monoxide. Alternatively, adenovirus-mediated overexpression of HO-1 attenuated the growth-inhibitory and inflammatory effect of PIs. In contrast, blocking HO-1 activity failed to modify the anti-migratory effect of the PIs. Thus, induction of HO-1 via the ROS–Nrf2 pathway in human ECs counteracts the anti-proliferative and inflammatory actions of PIs by generating bilirubin. Therapeutic approaches targeting HO-1 may provide a novel approach in preventing EC dysfunction and vascular disease in HIV-infected patients undergoing antiretroviral therapy.

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Section: Discussionsupporting

confidence: 90%

“…Current strategies for preventing PI-induced endothelial dysfunction and cardiovascular disease are limited and largely restricted to the use of statins [20,66,72]. However, HO-1 represents an attractive therapeutic target in averting PI-associated endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Heme oxygenase-1-derived bilirubin counteracts HIV protease inhibitor-mediated endothelial cell dysfunction

Liu

Durante

Peyton

et al. 2016

Free Radical Biology and Medicine

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“…Regarding insulin resistance, stavudine and zidovudine have been shown to induce insulin resistance in cultured adipocytes [28] as was indinavir [35,36]. Other PIs also induce insulin resistance in cultured adipocytes or endothelial cells as lopinavir and ritonavir, with a milder effect for boosted atazanavir and even milder for boosted darunavir [39,73]. Insulin resistance would lead to increased release of free fatty acids by adipose tissue, resulting in insulin resistance in the liver, heart, pancreas and the muscles, a process called lipotoxicity [74].…”

Section: Pathophysiologymentioning

confidence: 99%

Metabolic complications affecting adipose tissue, lipid and glucose metabolism associated with HIV antiretroviral treatment

Lagathu

Béréziat

Gorwood

et al. 2019

Expert Opinion on Drug Safety

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Introduction: Efficient antiretroviral-treatment(ART) generally allows control of HIV infection. However, persons-living-with-HIV(PLWH), when ageing, present a high prevalence of metabolic diseases. Area covered: Altered adiposity, dyslipidemias, insulin resistance, diabetes and their consequences are prevalent in PLWH and could be partly related to ART. Expert opinion: At first, personal and lifestyle factors are involved in the onset of these complications. The persistence of HIV in tissue reservoirs could synergize with some ART and enhance metabolic disorders. Altered fat repartition, diagnosed as lipodystrophy, has been related to first-generation nucleoside-reverse-transcriptase-inhibitors(NRTIs) (stavudine zidovudine) and some protease inhibitors(PIs). Recently, use of some integraseinhibitors(INSTI) resulted in weight/fat gain, which represents a worrisome unresolved situation.Lipid parameters were affected by some first-generation NRTIs, non-NRTIs(efavirenz) but also PIs boosted by ritonavir, with increased total and LDL-cholesterol and triglycerides.Insulin resistance is common in aging PLWH, often associated with abdominal obesity.Diabetes incidence, high with first-generation-ART (zidovudine, stavudine, didanosine, indinavir) has declined with contemporary ART close to that of the general population.Metabolic syndrome, a dysmetabolic situation with central obesity and insulin resistance, and liver steatosis are common in PLWH and could indirectly result from ART-associated fat gain and insulin resistance. All these dysmetabolic situations increase the atherogenic cardiovascular risk.Before 2000, PLWH received first-generation ART, as nucleoside analogue reverse transcriptase inhibitors (thymidine NRTIs, stavudine, zidovudine, didanosine) and protease inhibitors (PI, indinavir, ritonavir, nelfinavir) responsible for marked adverse events on lipid and glucose metabolism and on adipose tissue. These ART were replaced by newer molecules presenting a markedly lower metabolic toxicity.However, some PLWH, previously treated with first-generation NRTIs, present long-lasting fat alterations with metabolic consequences [1]. Some contemporary ART as integrase inhibitors (INSTI), considered as metabolic-friendly, were recently associated with weight/fat gain. Therefore, there are remaining and evolving concerns regarding the effect of ART on metabolism and adipose tissue in PLWH.As a consequence of the metabolic effects of some ART, increased prevalence of cardiovascular diseases (CVD), particularly atherosclerotic CVD[2] and diabetes, has been reported, but differ according to the calendar years and the geographic area. It is important to consider the metabolic profile of each patients to adapt ART. If required, classical lipid and glucose-lowering medications are prescribed.

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“…Both eNOS expression and NO production were decreased by LPV/r, while endothelin-1 (an endothelium-derived vasoconstrictor) expression was increased. Furthermore, the secretion of soluble ICAM or soluble VCAM (indicative of altered cell integrity) was increased~2-3 fold by LPV/r [104]. However, contrary to the above in vitro studies, a study investigating the effects of LPV/r in healthy, nonobese human subjects, failed to show evidence of endothelial dysfunction [105].…”

Section: Lopinavir and Ritonavirmentioning

confidence: 99%

Vascular endothelial dysfunction in the wake of HIV and ART

et al. 2018

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Mounting evidence points to increased rates of cardiovascular disease (CVD) among people living with HIV/AIDS (PLWHA). Endothelial dysfunction (loss of endothelium-dependent vascular relaxation in response to provasodilatory stimuli) constitutes an early pathophysiological event in atherogenesis and CVD. Both HIV-1 infection and antiretroviral therapy (ART) are implicated in the development of endothelial dysfunction; however, conclusions are frequently drawn from associations shown in epidemiological studies. In this narrative review of mainly in vitro and animal studies, we report on the current understanding of how various HIV-1 proteins, HIV-1-induced proinflammatory cytokines and common antiretroviral drugs directly impact vascular endothelial cells. Proposed cellular mechanisms underlying the switch to a dysfunctional state are discussed, including oxidative stress, impaired expression and regulation of endothelial nitric oxide (NO) synthase (eNOS) and increased expression of vascular adhesion molecules. From the literature, it appears that increased reactive oxygen species (ROS) production, linked to decreased NO bioavailability and ensuing endothelial dysfunction, may be proposed as a putative final common pathway afflicting the vascular endothelium in PLWHA. The HIV-1-proteins Tat, Gp120 and Nef in particular, the proinflammatory cytokine, TNF-α, and the antiretroviral drugs Efavirenz and Lopinavir, most commonly postulated to be primary causal agents of endothelial dysfunction, are also discussed. We conclude that, despite existing evidence from basic research papers, a significant gap remains in terms of the exact underlying cellular mechanisms involved in HIV-1 and ART induced endothelial dysfunction. Bridging this gap could help pave the way for future strategies to prevent and treat early cardiovascular changes in PLWHA.

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Impact of Darunavir, Atazanavir and Lopinavir Boosted with Ritonavir on Cultured Human Endothelial Cells: Beneficial Effect of Pravastatin

Cited by 35 publications

References 57 publications

Heme oxygenase-1-derived bilirubin counteracts HIV protease inhibitor-mediated endothelial cell dysfunction

Heme oxygenase-1-derived bilirubin counteracts HIV protease inhibitor-mediated endothelial cell dysfunction

Metabolic complications affecting adipose tissue, lipid and glucose metabolism associated with HIV antiretroviral treatment

Vascular endothelial dysfunction in the wake of HIV and ART

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