title: HIV-Tat protein induces oxidative and inflammatory pathways in brain endothelium.
abstract: Impaired function of the brain vasculature might contribute to the development of HIV-associated dementia. For example, injury or dysfunction of brain microvascular endothelial cells (BMEC) can lead to the breakdown of the blood-brain barrier (BBB) and thus allow accelerated entry of the HIV-1 virus into the CNS. Mechanisms of injury to BMEC during HIV-1 infection are not fully understood, but the viral gene product Tat may be, at least in part, responsible for this effect. Tat can be released from infected perivascular macrophages in the CNS of patients with AIDS, and thus BMEC can be directly exposed to high concentrations of this protein. To study oxidative and inflammatory mechanisms associated with Tat-induced toxicity, BMEC were exposed to increasing doses of Tat1-72, and markers of oxidative stress, as well as redox-responsive transcription factors such as nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), were measured. Tat1-72 treatment markedly increased cellular oxidative stress, decreased levels of intracellular glutathione and activated DNA binding activity and transactivation of NF-kappaB and AP-1. To determine if Tat1-72 can stimulate inflammatory responses in brain endothelium in vivo, expression of monocyte chemoattractant protein-1 (MCP-1), an NF-kappaB and AP-1-dependent chemokine, was studied in brain tissue in mice injected with Tat1-72 into the right hippocampus. Tat1-72 markedly elevated the MCP-1 mRNA levels in brain tissue. In addition, a double immunohistochemistry study revealed that MCP-1 protein was markedly overexpressed on brain vascular endothelium. These data indicate that Tat1-72 can induce redox-related inflammatory responses both in in vitro and in vivo environments. These changes can directly lead to disruption of the BBB. Thus, Tat can play an important role in the development of detrimental vascular changes in the brains of HIV-infected patients.
authors.affiliation: Department of Surgery, Animal Sciences and Neurology, University of Kentucky Medical Center, Lexington, Kentucky 40536, USA. mjtobo00@pop.uky.edu
authors.forename: Michal
authors.initials: M
authors.lastname: Toborek
authors.forename: Yong Woo
authors.initials: YW
authors.lastname: Lee
authors.forename: Hong
authors.initials: H
authors.lastname: Pu
authors.forename: Andrzej
authors.initials: A
authors.lastname: Malecki
authors.forename: Govinder
authors.initials: G
authors.lastname: Flora
authors.forename: Rosario
authors.initials: R
authors.lastname: Garrido
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hennig
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Bauer
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
mesh_terms: D000818:Animals; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D018932:Chemokine CCL2 / Q000235:genetics; D002999:Clone Cells; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D015696:Gene Products, tat / Q000494:pharmacology*; D008833:Microcirculation / Q000187:drug effects; D016328:NF-kappa B / Q000502:physiology; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D013552:Swine; D018808:Transcription Factor AP-1 / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects; D014657:Vasculitis / Q000139:chemically induced* / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D018932:Chemokine CCL2; D015696:Gene Products, tat; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D054322:tat Gene Products, Human Immunodeficiency Virus; C470431:tat peptide (1-72), Human immunodeficiency virus 1