Premature Senescence of Vascular Cells Is Induced by HIV Protease Inhibitors

Abstract

Objective-To determine whether and how protease inhibitors (PIs) could affect vascular aging. Methods and Results-HIV therapy with PIs is associated with an increased risk of premature cardiovascular disease. The effect of ritonavir and a combination of lopinavir and ritonavir (for 30 days) on senescence, oxidative stress, and inflammation was evaluated in human coronary artery endothelial cells (HCAECs Key Words: endothelial cell Ⅲ PBMC Ⅲ HIV protease inhibitor Ⅲ aging Ⅲ prelamin A Ⅲ statin Ⅲ antioxidants T he increased risk of premature myocardial infarction observed in HIV-infected patients has been attributed to antiretroviral therapy, HIV infection itself, and a synergistic interaction between these factors and other classic cardiovascular risk factors. 1-4 Antiretroviral therapy may promote premature cardiovascular disease through endothelial dysfunction either indirectly, via protease inhibitor (PI)-induced metabolic disturbances; or directly, via alterations of endothelial cells. 5-8 Accordingly, several endothelial cell functions, including production of reactive oxygen species (ROS) and secretion of inflammatory cytokines, can be deregulated by short-term exposure (24 to 72 hours) of cultured endothelial cells to ritonavir or other PIs. 8 -12 The risk of premature cardiovascular events might also result from the accelerated biological aging imposed by antiretroviral therapy and/or HIV itself. [13][14][15][16] Indeed, vascular endothelial cell dysfunction is a feature of the human physiological aging process, 17,18 and syndromes of premature aging are associated with precocious cardiovascular disease. The most striking findings are observed in progeroid syndromes linked to molecular alterations in the prelamin A maturation process. 19 -22 In these genetically determined accelerated aging phenotypes, both vascular endothelial and smooth muscle cells (VSMCs) are altered. 20,23 They exhibit senescent morphological features at the cellular and nuclear levels and aging-related dysfunctions linked to prelamin A accumulation. [23][24][25] Prelamin A accumulation is also observed in VSMCs during physiological aging and in atherosclerotic lesions, where it often colocalized with senescent and degenerate VSMCs. 26 The physiological posttranslational processing of prelamin A is complex, leading to the production of mature lamin A, a ubiquitous protein of the nuclear lamina meshwork. The 2 major steps are catalyzed by a farnesyl transferase, which

Lipodystrophy-Linked LMNA p.R482W Mutation Induces Clinical Early Atherosclerosis and In Vitro Endothelial Dysfunction

“…22 Our group previously reported that HIV protease inhibitors, known to inhibit ZMPSTE24, 47 induced an accumulation of farnesylated prelamin-A in endothelial cells and that the inhibition of prelamin-A farnesylation by pravastatin treatment improved endothelial dysfunction in this model. 33 We demonstrated here that pravastatin treatment in vitro also decreased the amount of p.R482W farnesylated prelamin-A, improved endothelial dysfunction and oxidative stress, and reduced the occurrence of DNA damages in HCAECs. Moreover, we observed that antioxidant treatments reduced the secretion of inflammatory and adhesion molecules and decreased DNA DSBs in HCAECs overexpressing p.R482W-prelamin-A.…”

“…29,30 In endothelial cells, oxidative stress was shown to impair NO biodisponibility and to promote inflammation, leukocyte adhesion, and cellular senescence. [31][32][33][34] In addition, DNA damages were observed in atherosclerotic lesions of patients with coronary heart diseases in vivo and linked with oxidative stress in vitro. 35 Thus, we hypothesized that abnormal accumulation of farnesylated p.R482-prelamin-A in the cells of patients with FPLD2 could result in endothelial cell dysfunction and senescence that, in addition to metabolic risk factors, could be important pathogenic events leading to premature atherosclerosis in these patients.…”

Cardiovascular Disease, Statins, and HIV

“…PIs have been associated with dyslipidemia and metabolic derangements that then contribute in a complicated interplay to affect inflammation and immune activation, as discussed in greater depth by Koethe et al elsewhere in this supplement [24]. PIs have also been shown to trigger premature senescence in endothelial cells and circulating peripheral blood mononuclear cells (PBMCs) of PI-treated HIV-infected patients [25]. However, it should be noted that newer PIs have not demonstrated a clear association with inflammation when compared to other non-PI therapies [26].…”

“…Indeed, the possible negative effects of statins were expressed as a concern in a letter by Corrales Finally, data suggest that statins improve the cellular senescence phenotype in PI-treated endothelial cells and patient PBMCs [25]. This may offer another mechanism by which statins improve immune and/or endothelial dysfunction in HIV-infected patients.…”

Kidney failure during HIV disease treated with tenofovir, multiple concurrent diseases and drug therapies

“…In our special case report, waiting for a large employment of nucleos(t)ide sparing cART regimens and that of regimens completely relying on agents other than nucleos(t)ide and non-nucleoside analogue reverse transcriptase inhibitors, which are still not so widely employed in patients showing an excellent and sustained response to other cART regimens [82], due to their still incomplete indications and often elevated costs [11,[133][134][135], we had to select which was the most effective, and "comfortable" classic third agent for our patient. Since we were forced to eliminate immediately all available non-nucleoside reverse transcriptase inhibitors due to the former adverse cutaneous and CNS reaction to efavirenz, and a large portion of HIV protease inhibitors remained fully effective to our unfortunate patient, who never failed a cART regimen in his prolonged follow-up, in order to accompany the finally maintained tenofovir-emtricitabine nucleos(t)ide backbone, we selected the effective, safe, and convenient darunavir (at 800 mg once daily) plus a minimum ritonavir booster dosage (100 mg), after considering that the acute kidney event occurred under fosamprenavir-ritonavir combination, the atazanavir-ritonavir association was not tolerated due to a trivial but persistant hyperbilirubinemia, lopinavir-ritonavir has a well known unfavorable dyslipidemic profile, and novel profiles of risk are at the horizon in patients receiving protease inhibitor-based cART regimens [136], but may be controlled by statins, too, especially when a patient at very elevated risk of repeated major vascular events is of concern. As known since many years, the HIV protease inhibitors may be easily "sequenced" on both a tolerability and an efficacy point of view [137][138][139].…”