title: HIV Tat induces expression of ICAM-1 in HUVECs: implications for miR-221/-222 in HIV-associated cardiomyopathy.
abstract: Cardiac involvement is a well-documented complication of human immunodeficiency virus-1 (HIV-1) infection. Previous studies have demonstrated increased adhesion of monocytes to human vascular endothelial cells in HIV-infected individuals. HIV Tat protein, which is the transactivator of transcription (Tat), plays a key role in activating endothelial cells. In the present study, we demonstrated that exposure of HUVECs to HIV Tat protein resulted in induced expression of cell adhesion molecules specifically ICAM-1, leading to increased adhesion of monocytes to the endothelium. This effect of Tat was mediated through activation of mitogen-activated protein kinases and downstream transcription factor NF-κB. Increased expression of ICAM-1 was regulated by microRNA (miRNA) miR-221 and to some extent by miR-222, both of which are known to target ICAM-1. Functional inhibition of the respective miRNAs with anti-miR oligonucleotides resulted in induction of ICAM-1 protein in HUVECs. Furthermore, Tat-stimulated regulation of ICAM-1 via miR-221/-222 involved the NF-kB-dependent pathway. Functional implication and specificity of up-regulated ICAM-1 was confirmed using the ICAM-1 neutralizing antibody in the in vitro cell adhesion assays. These findings were further confirmed in vivo using the HIV transgenic (Tg) rats. These animals not only demonstrated increased expression of ICAM-1 mRNA, with a concomitant reduction in the expression of miR-221 in the aorta and heart, but also had increased expression of the ICAM-1 protein that was predominantly in the endothelial cell layer. Taken together, these findings implicate that Tat-mediated induction of ICAM-1 expression plays a critical role in monocyte adhesion observed in HIV-1-associated cardiomyopathies.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Duan
authors.forename: Honghong
authors.initials: H
authors.lastname: Yao
authors.forename: Guoku
authors.initials: G
authors.lastname: Hu
authors.forename: XianMing
authors.initials: X
authors.lastname: Chen
authors.forename: Amie K
authors.initials: AK
authors.lastname: Lund
authors.forename: Shilpa
authors.initials: S
authors.lastname: Buch
mesh_terms: D000818:Animals; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D018799:Intercellular Adhesion Molecule-1; D035683:MicroRNAs; D054322:tat Gene Products, Human Immunodeficiency Virus; C525709:MIR221, human; C525710:MIR222, human
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