HIV Protein Tat Induces Macrophage Dysfunction and Atherosclerosis Development in Low-Density Lipoprotein Receptor–Deficient Mice

Zhaojie Meng, Rebecca Hernandez, Jingwei Liu, Taesik Gwag, Weiwei Lu, Tzung K. Hsiai, Marcus Kaul, Tong Zhou, Changcheng Zhou

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Purpose: 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. Methods: To investigate the effects of Tat on macrophage IKKβ activation and atherosclerosis development in vivo, myeloid-specific IKKβ-deficient LDLR-deficient (IKKβΔMyeLDLR−/−) mice and their control littermates (IKKβF/FLDLR−/−) were exposed to recombinant HIV protein Tat. Results: Exposure to Tat significantly increased atherosclerotic lesion size and plaque vulnerability in IKKβF/FLDLR−/− but not IKKβΔMyeLDLR−/− mice. Deficiency of myeloid IKKβ attenuated Tat-elicited macrophage inflammatory responses and atherosclerotic lesional inflammation in IKKβΔMyeLDLR−/− mice. Further, RNAseq analysis demonstrated that HIV protein Tat affects the expression of many atherosclerosis-related genes in vitro in an IKKβ-dependent manner. Conclusions: Our findings reveal atherogenic effects of HIV protein Tat in vivo and demonstrate a pivotal role of myeloid IKKβ in Tat-driven atherogenesis.

Original languageEnglish (US)
Pages (from-to)201-215
Number of pages15
JournalCardiovascular Drugs and Therapy
Volume36
Issue number2
DOIs
StatePublished - Apr 2022
Externally publishedYes

Keywords

  • Atherosclerosis
  • HIV infection
  • Inflammation
  • IκB kinase β
  • Macrophages
  • Nuclear factor-κB

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine
  • Pharmacology (medical)

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