Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA, USA.
Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY, USA.
Cardiovasc Drugs Ther. 2022 Apr;36(2):201-215. doi: 10.1007/s10557-021-07141-x. Epub 2021 Jan 18.
HIV infection is consistently associated with an increased risk of atherosclerotic cardiovascular disease, but the underlying mechanisms remain elusive. HIV protein Tat, a transcriptional activator of HIV, has been shown to activate NF-κB signaling and promote inflammation in vitro. However, the atherogenic effects of HIV Tat have not been investigated in vivo. Macrophages are one of the major cell types involved in the initiation and progression of atherosclerosis. We and others have previously revealed the important role of IκB kinase β (IKKβ), a central inflammatory coordinator through activating NF-κB, in the regulation of macrophage functions and atherogenesis. This study investigated the impact of HIV Tat exposure on macrophage functions and atherogenesis.
To investigate the effects of Tat on macrophage IKKβ activation and atherosclerosis development in vivo, myeloid-specific IKKβ-deficient LDLR-deficient (IKKβLDLR) mice and their control littermates (IKKβLDLR) were exposed to recombinant HIV protein Tat.
Exposure to Tat significantly increased atherosclerotic lesion size and plaque vulnerability in IKKβLDLR but not IKKβLDLR mice. Deficiency of myeloid IKKβ attenuated Tat-elicited macrophage inflammatory responses and atherosclerotic lesional inflammation in IKKβLDLR mice. Further, RNAseq analysis demonstrated that HIV protein Tat affects the expression of many atherosclerosis-related genes in vitro in an IKKβ-dependent manner.
Our findings reveal atherogenic effects of HIV protein Tat in vivo and demonstrate a pivotal role of myeloid IKKβ in Tat-driven atherogenesis.
HIV 感染始终与动脉粥样硬化性心血管疾病风险增加相关，但潜在机制仍不清楚。HIV 蛋白 Tat 是 HIV 的转录激活物，已被证明可在体外激活 NF-κB 信号并促进炎症。然而，HIV Tat 的动脉粥样硬化作用尚未在体内进行研究。巨噬细胞是参与动脉粥样硬化起始和进展的主要细胞类型之一。我们和其他人之前已经揭示了 IκB 激酶β（IKKβ）在调节巨噬细胞功能和动脉粥样硬化形成中的重要作用，IKKβ 是通过激活 NF-κB 来协调炎症的关键因子。本研究探讨了 HIV Tat 暴露对巨噬细胞功能和动脉粥样硬化形成的影响。
为了研究 Tat 对体内巨噬细胞 IKKβ 激活和动脉粥样硬化发展的影响，我们使用骨髓细胞特异性 IKKβ 缺陷 LDLR 缺陷（IKKβLDLR）小鼠及其对照同窝仔（IKKβLDLR）进行了实验。
暴露于 Tat 显著增加了 IKKβLDLR 但不是 IKKβLDLR 小鼠的动脉粥样硬化病变大小和斑块易损性。骨髓细胞 IKKβ 缺陷减弱了 Tat 诱导的 IKKβLDLR 小鼠巨噬细胞炎症反应和动脉粥样硬化病变炎症。此外，RNAseq 分析表明，HIV 蛋白 Tat 以 IKKβ 依赖的方式影响体外许多动脉粥样硬化相关基因的表达。
我们的发现揭示了 HIV 蛋白 Tat 在体内的动脉粥样硬化作用，并证明了骨髓细胞 IKKβ 在 Tat 驱动的动脉粥样硬化形成中的关键作用。
