Molecular Mechanisms of HIV Protease Inhibitor-Induced Endothelial Dysfunction

Abstract

Highly active antiretroviral therapy incorporating protease inhibitors (PIs) is successful in controlling HIV infection and has dramatically improved the prognosis of HIV-infected patients. The therapeutic benefit of long-term use of HIV PIs is compromised by an increased risk of cardiovascular disease, however, including metabolic syndrome and endothelial dysfunction. Although clinical evidence strongly suggests an association of the use of HIV PIs with endothelial dysfunction, the underlying molecular mechanisms have not been fully elucidated yet. In this review, we describe recent advances in the molecular mechanisms of PI-induced endothelial dysfunction. The available evidence demonstrates that certain HIV PIs could induce endothelial dysfunction, including a decrease of endothelium-dependent vasorelaxation, inhibition of the nitric oxide synthase system, increase of oxidative stress, and activation of mitogen-activated protein kinases. HIV infection itself may also induce endothelial dysfunction and injury. These new discoveries provide a better understanding of the molecular mechanisms of the interaction between HIV PIs and vascular cells and may suggest potential approaches to control HIV PI-associated cardiovascular complications.

State of the Science Conference

“…The potential mechanisms by which specific PI-based regimens can adversely affect endothelial function, include reduction in nitric oxide production or release, increases in reactive oxygen species (41,42), impairment of cholesterol efflux from foam cells and increased macrophage cholesterol ester accumulation through upregulation of CD36 scavenge receptor (43,44). Specific NRTI's, including stavudine and zidovudine may also increase superoxide production in experimental models (45).…”

Premature Senescence of Vascular Cells Is Induced by HIV Protease Inhibitors

“…These PIs were selected because they display proatherogenic lipid profiles in HIV-infected patients 37,38 and induce short-term endothelial cell dysfunction in experimental studies. [7][8][9][10][11] In HCAECs, PIs decreased cell proliferation and division, increased protein expression of cell cycle blockers and SA-␤-galactosidase activity, and altered cell and nuclear morphological features. They also increased ROS production and induced oversecretion of inflammation markers.…”

“…[1][2][3][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][6][7][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.…”

Pvuii Genetic Polymorphism of Low Density Lipoprotein Receptorin Human Immunodeficiency Virus Type 1-Infected Patients: Possible Association with Dyslipidemia

“…PIs-associated dyslipidemia is a frequent class -related event and can limit their use especially in patients with preexisting increased cardiovascular risk. Different mechanisms are involved in the PIs-associated dyslipidemia, including the decreased expression of the LDLR [25,37,40,41].…”