MicroRNA Regulation of Endothelial Progenitor Senescence in HIV Infection

DESCRIPTION（由申请人提供）：人类免疫缺陷病毒-1 （HIV）感染加速细胞和机体老化，并大大增加动脉粥样硬化的风险。内皮祖细胞（Endothelial progenitor cells， EPC）积极参与血管稳态和动脉修复，并能预测心血管事件。衰老的EPC修复能力受损，这与动脉粥样硬化的发展有关。HIV感染对EPC的影响及其潜在机制仍有待阐明。MicroRNAs （miRNA）调控体细胞的衰老。我们已经通过基因组筛选确定了miR-10A*、miR-21、miR-146a、miR-29c和miR-126，以及它们的靶基因在年轻和年老的EPC/谱系阴性骨髓细胞（lin- BMC）中存在差异表达。此外，我们已经证明这些miRNA/靶基因分离成三个miRNA信号轴，控制EPC/lin- BMC的不同基本过程。

DESCRIPTION (provided by applicant): Human immunodeficiency virus-1 (HIV) infection accelerates cellular and organismal aging and substantially increases the risk of atherosclerosis. Endothelial progenitor cells (EPC) are actively involved in vascular homeostasis and arterial repair and can predict cardiovascular events. Senescent EPC have impaired repair capacity, which is associated with atherosclerosis development. The impact of HIV infection on EPC and the underlying mechanisms remain to be elucidated. MicroRNAs (miRNA) regulate the senescence of somatic stem cells. We have identified miR-10A*, miR-21, miR-146a, miR-29c and miR-126, as well as, their target genes, to be differentially expressed in young and old EPC/lineage negative bone marrow cells (lin- BMC) using genomic screening. Furthermore, we have demonstrated that these miRNA/target genes segregate into three miRNA signaling axes that control different basic processes of EPC/lin- BMC. Specifically, miR- 10A*/miR-21 —↓hmga2 —↑p16Ink4a/p19Arf mainly regulates cell self-renewal; miR-146a —↓Plk2 pathway chiefly controls cell apoptosis; and miR-29c —↓klf2a —↓miR-126 —↑spred-1 —↓VEGF signaling predominantly governs differentiation, respectively. In addition, we have shown that modifying these three pathways can dramatically impact the senescence and the angiogenic and vascular repair capacity of EPC. The primary objective of the current proposal is to understand the impact of HIV infection on the circulating levels and functionality of EPC and the underlying mechanisms. Our central hypotheses are that HIV infection is associated with EPC senescence, which contributes to accelerated atherogenesis, and that the specific miRNA regulatory networks mediate this process. We will test these proof-of-principle hypotheses by examining the EPC levels in well- characterized clinical samples using multiple standardized approaches/techniques and testing their functionality using established cell culture procedures. We will further determine the role of candidate miRNA regulatory networks in mediating the effects of HIV on EPC functions. Results from these studies will offer understanding of EPC changes and the underlying molecular mechanisms in the pathogenesis of HIV- associated accelerated atherosclerosis, and may open an avenue for facilitating the design of novel therapeutic strategies for HIV-associated cardiovascular disease.