Cell Death and Disease
Neuronal damage is a hallmark feature of HIV-associated neurological disorders (HANDs). Opiate drug abuse accelerates the incidence and progression of HAND; however, the mechanisms underlying the potentiation of neuropathogenesis by these drugs remain elusive. Opiates such as morphine have been shown to enhance HIV transactivation protein Tat-mediated toxicity in both human neurons and neuroblastoma cells. In the present study, we demonstrate reduced expression of the tropic factor platelet-derived growth factor (PDGF)-B with a concomitant increase in miR-29b in the basal ganglia region of the brains of morphine-dependent simian immunodeficiency virus (SIV)-infected macaques compared with the SIV-infected controls. In vitro relevance of these findings was corroborated in cultures of astrocytes exposed to morphine and HIV Tat that led to increased release of miR-29b in exosomes. Subsequent treatment of neuronal SH-SY5Y cell line with exosomes from treated astrocytes resulted in decreased expression of PDGF-B, with a concomitant decrease in viability of neurons. Furthermore, it was shown that PDGF-B was a target for miR-29b as evidenced by the fact that binding of miR-29 to the 3'-untranslated region of PDGF-B mRNA resulted in its translational repression in SH-SY5Y cells. Understanding the regulation of PDGF-B expression may provide insights into the development of potential therapeutic targets for neuronal loss in HIV-1-infected opiate abusers.
3' Untranslated Regions, Analgesics, Opioid, Animals, Astrocytes, Cells, Cultured, Disease Models, Animal, Down-Regulation, Exosomes, Ganglia, Gene Expression Regulation, Humans, Macaca mulatta, MicroRNAs, Morphine, Neurons, Proto-Oncogene Proteins c-sis, Rats, Simian immunodeficiency virus, Transfection, tat Gene Products, Human Immunodeficiency Virus
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Hu, Guoku; Yao, H; Chaudhuri, A D.; Yelamanchili, Sowmya V.; Wen, H; Cheney, P D.; Fox, Howard S.; and Buch, Shilpa J., "Exosome-mediated shuttling of microRNA-29 regulates HIV Tat and morphine-mediated neuronal dysfunction." (2012). Journal Articles: Pharmacology & Experimental Neuroscience. Paper 8.