TY - JOUR
T1 - Molecular programming of endothelin-1 in HIV-infected brain
T2 - Role of Tat in up-regulation of ET-1 and its inhibition by statins
AU - Chauhan, Ashok
AU - Hahn, Sven
AU - Gartner, Suzanne
AU - Pardo, Carlos A.
AU - Netesan, Senthil Kumar
AU - McArthur, Justin
AU - Nath, Avindra
PY - 2007/3
Y1 - 2007/3
N2 - Human Immune Deficiency Virus-1 (HIV-1) infection can induce severe and debilitating neurological problems, including behavioral abnormalities, motor dysfunction, and dementia. HIV can persistently infect astrocytes, during which viral accessory proteins are produced that are unaffected by current antiretroviral therapy. The effect of these proteins on astrocyte function remains unknown. Astrocytes are the predominant cells within the brain; thus, disruption of astrocyte function could influence the neuropathogenesis of HIV infection. To explore further these effects, we constitutively expressed HIV-Tat protein in astrocytes. Since the nuclear presence of Tat protein leads to alteration of host gene expression, we further analyzed the effects of Tat on host gene transcripts. Endothelin-1 (ET-1) was a significantly elevated transcript as verified by reverse transcription-polymerase chain reaction (RT-PCR), and it was subsequently released extracellularly in Tat-expressing and HIV-infected astrocytes. ET-1 expression was also prominent in reactive astrocytes and neurons in brain tissues from basal ganglia and frontal lobes of HIV encephalitic patients. HIV-Tat regulated ET-1 at the transcriptional level through NF-κB (NF-κB)-responsive sites in the ET-1 promoter. Intriguingly, simvastatin (10 μM) down-regulated HIV-Tat-induced ET-1 and also inhibited activation of NF-κB in astrocytes. Our findings suggest that ET-1 may be critical in mediating the neuropathogenesis of HIV dementia and that statins may have therapeutic potential in these patients.
AB - Human Immune Deficiency Virus-1 (HIV-1) infection can induce severe and debilitating neurological problems, including behavioral abnormalities, motor dysfunction, and dementia. HIV can persistently infect astrocytes, during which viral accessory proteins are produced that are unaffected by current antiretroviral therapy. The effect of these proteins on astrocyte function remains unknown. Astrocytes are the predominant cells within the brain; thus, disruption of astrocyte function could influence the neuropathogenesis of HIV infection. To explore further these effects, we constitutively expressed HIV-Tat protein in astrocytes. Since the nuclear presence of Tat protein leads to alteration of host gene expression, we further analyzed the effects of Tat on host gene transcripts. Endothelin-1 (ET-1) was a significantly elevated transcript as verified by reverse transcription-polymerase chain reaction (RT-PCR), and it was subsequently released extracellularly in Tat-expressing and HIV-infected astrocytes. ET-1 expression was also prominent in reactive astrocytes and neurons in brain tissues from basal ganglia and frontal lobes of HIV encephalitic patients. HIV-Tat regulated ET-1 at the transcriptional level through NF-κB (NF-κB)-responsive sites in the ET-1 promoter. Intriguingly, simvastatin (10 μM) down-regulated HIV-Tat-induced ET-1 and also inhibited activation of NF-κB in astrocytes. Our findings suggest that ET-1 may be critical in mediating the neuropathogenesis of HIV dementia and that statins may have therapeutic potential in these patients.
KW - ET-1 transcriptional regulation
KW - HIV-neuropathogenesis
KW - NF-κB
KW - Nuclear Tat
KW - Simvastatin
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U2 - 10.1096/fj.06-7054com
DO - 10.1096/fj.06-7054com
M3 - Article
C2 - 17197385
AN - SCOPUS:33847408485
SN - 0892-6638
VL - 21
SP - 777
EP - 789
JO - FASEB Journal
JF - FASEB Journal
IS - 3
ER -