Impact of CCR5, Integrase and Protease Inhibitors on Human Endothelial Cell Function, Stress, Inflammation and Senescence
Abstract
Background: Ageing HIV-infected patients present an increased incidence of cardiovascular diseases, endothelial dysfunction being an early alteration. Some protease inhibitors (PIs) have been shown to increase the risk of cardiovascular disease. We evaluated here the effects of CCR5 or integrase inhibitors as compared to PIs on endothelial functions in vitro. Methods: Human coronary artery endothelial cells (HCAEC) from adult and old non-HIV-infected donors were treated for 15 days with the CCR5 inhibitor mara-viroc, the integrase inhibitors dolutegravir or raltegravir or the ritonavir-boosted PIs, darunavir (DRV/r) or atazanavir (ATV/r), all at C max concentrations. We evaluated endothelial function, secretion of adhesion molecules and cytokines, inflammation, oxidative stress and senescence. Results: In endothelial cells from adult donors, we con-firmed that ATV/r and DRV/r adversely affected all assessed endothelial functions and enhanced senescence, these effects being mild for DRV/r. Raltegravir had no effect and maraviroc a mild anti-inflammatory effect. Dolutegravir decreased inflammation, by inhibiting the NFκB pathway, and senescence, by repressing the p21 pathway. Moreover, HCAEC from an old donor presented, constitutively, a high level of senescence. Raltegravir mildly affected inflammation and senescence while maraviroc and dolutegravir decreased oxidative stress, inflammation and senescence and improved endothelial dysfunction. Conclusions: We report here that the integrase inhibitor dolutegravir and the CCR5 inhibitor maraviroc reduced inflammation of human adult endothelial cells to different extents while raltegravir was neutral. Dolutegravir also reduced senescence, while PI/r increased inflammation and senescence. It is important to address the clinical relevance of these results.
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Protease inhibitors induce senescence in human arterial endothelial cells in vitro.
“Protease inhibitors are reported to induce senescence in human arterial endothelial cells in vitro.”
From The struggle of a good friend getting old: cellular senescence in viral responses and therapy (2021) · cites this paper as Afonso et al, 2017
Senescent human arterial endothelial cells induced by protease inhibitors display reduced e-NOS expression and increased VCAM-1 secretion.
“Importantly, these senescent cells displayed reduced expression of endothelial nitric oxide synthase (e‐NOS), an enzyme responsible for NO synthesis, and increased secretion of VCAM‐1 (Lefèvre et al, 2010; Auclair et al, 2014; Afonso et al, 2017).”
From The struggle of a good friend getting old: cellular senescence in viral responses and therapy (2021) · cites this paper as Afonso et al, 2017
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- Authors
- Afonso, P., Auclair, M., Caron-Debarle, M., & Capeau, J.
- Affiliations
- Inserm (FR)
- Sorbonne Universités, UPMC Univ Paris 6, Paris, France
- Corresponding author
- Capeau, Jacqueline
- Venue
- Antiviral Therapy
- Publisher
- SAGE Publications
- Published
- 2016-11-01
- Volume
- 22
- Issue
- 8
- Pages
- 645-657
- ISSN
- 1359-6535 (ISSN-L)
- 2040-2058
- OpenAlex
- W2601903444
- Cited by
- 28
- References
- 45
- Citations by year
- 2025: 5 · 2024: 2 · 2022: 4 · 2021: 9 · 2020: 4 · 2019: 1 · 2018: 3
- FWCI
- 1.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Antiviral Therapy (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Health Sciences › Medicine › Emergency Medicine › HIV-related health complications and treatments
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Keywords
- CCR5 antagonist, integrase inhibitors, protease inhibitors, endothelial dysfunction, endothelial cell senescence, inflammation, oxidative stress, HIV, dolutegravir, maraviroc, raltegravir, atazanavir, darunavir, NF-κB signaling, p21, adhesion molecules, cardiovascular disease, aging
- MeSH terms
- Adult, Aged, 80 and over, Humans, Male, Oxidation-Reduction, Stress, Physiological, Cell Adhesion Molecules, Cytokines, Cellular Senescence, HIV Protease Inhibitors, Reactive Oxygen Species, Oxidative Stress, Inflammation Mediators, Anti-HIV Agents, HIV Integrase Inhibitors, Endothelial Cells, Cell Cycle Checkpoints, CCR5 Receptor Antagonists
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