Abstract
Both HIV and antiretroviral therapy could induce vascular aging with unclear mechanisms. In this study, via microarray analysis, we identified, for the first time, that miR-34a expression was significantly increased in both HIV-infected, and antiretroviral agents-treated vessels and vascular endothelial cells (ECs) from these vessels. In cultured ECs, miR-34a expression was significantly increased by HIV-Tat protein and by the antiretroviral agents, lopinavir/ritonavir. Both HIV-Tat protein and antiretroviral agents could induce EC senescence, which was inhibited by miR-34a inhibition. In contrast, EC senescence was exacerbated by miR-34a overexpression. In addition, the vascular ECs isolated from miR-34a knockout mice were resistant to HIV and antiretroviral agents-mediated senescence. In vivo, miR-34a expression in mouse vascular walls and their ECs was increased by antiretroviral therapy and by HIV-1 Tat transgenic approach. miR-34a inhibition could effectively inhibit both HIV-Tat protein and antiretroviral therapy-induced vascular aging in mice. The increased miR-34a was induced via p53, whereas Sirt1 was a downstream target gene of miR-34a in both HIV-Tat protein and antiretroviral agents-treated ECs and vessels. The study has demonstrated that miR-34a is a common link in both HIV and antiretroviral therapy-mediated vascular aging.
Highlights
Active antiretroviral therapy (HAART) has greatly reduced the risk of early death from opportunistic infections and extended the lifespan of people infected with immunodeficiency virus (HIV)
MicroRNAs are a class of endogenous, small, non-coding RNAs that inhibit the expression of the protein coding genes via degradation or translational inhibition of their target messenger RNAs [9]. miRNAs are highly expressed in the vascular system
By crossing-analysis of miRNA profiles of human and mouse arteries, and vascular endothelial cells (ECs), with HIV-infection or antiretroviral therapy, we identified that miR-34a expression is significantly increased in both HIVinfected, and antiretroviral agents, ritonavir and lopinavir-treated vessels and cells
Summary
Active antiretroviral therapy (HAART) has greatly reduced the risk of early death from opportunistic infections and extended the lifespan of people infected with immunodeficiency virus (HIV). Cardiovascular complications in the HIVinfected population emerge due to the increased survival [1]. Both HIV and antiretroviral therapy could exacerbate vascular aging and its related cardiovascular diseases such as atherosclerosis, coronary artery disease and stroke [2,3,4]. The studies from our group and others have demonstrated that miRNAs may play important roles in vascular biology, vascular aging and vascular disease [10, 11]. The biological roles of miRNAs in both HIV and antiretroviral therapymediated vascular aging have not been explored
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