Contents - College of Medical and Dental Sciences - University of ...
Contents - College of Medical and Dental Sciences - University of ...
Contents - College of Medical and Dental Sciences - University of ...
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The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK<br />
Pathogenesis Abstract 19<br />
KAPOSI'S SARCOMA ASSOCIATED HERPES VIRUS (KSHV/HHV-8) INDUCES<br />
ANGIOGENIN DURING INFECTION OF HUMAN DERMAL MICROVASCULAR<br />
ENDOTHELIAL (HMVEC-D) CELLS THAT IS CRITICAL FOR ANTI-APOPTOSIS,<br />
CELL PROLIFERATION AND ANGIOGENESIS<br />
Sathish Sadagopan, Neelam-Sharma Walia, Mohanan Valiya Veettil, Virginie Bottero, Rita<br />
Levine <strong>and</strong> Bala Ch<strong>and</strong>ran<br />
H.M. Bligh cancer research laboratories, Department <strong>of</strong> Microbiology <strong>and</strong> Immunology,<br />
Chicago <strong>Medical</strong> School, Rosalind Franklin <strong>University</strong> <strong>of</strong> Medicine <strong>and</strong> Science, Chicago, IL<br />
Abstract<br />
De novo KSHV infection <strong>of</strong> HMVEC-d cells results in increased expression <strong>and</strong> secretion <strong>of</strong><br />
angiogenin, a multifunctional angiogenic protein. KS tissue sections were positive for<br />
angiogenin highlighting the importance <strong>of</strong> angiogenin in KS pathogenesis. Viral gene<br />
expression was critical for the sustained angiogenin secretion during primary infection.<br />
KSHV ORF 73 (latent) <strong>and</strong> ORF 74 (lytic) genes induced an increased secretion <strong>of</strong><br />
angiogenein. TIVE cells latently infected with KSHV secreted high levels <strong>of</strong> angiogenin.<br />
Angiogenin bound to surface actin, internalized in a microtubule independent manner,<br />
translocated into the nucleus when the cells were semi-confluent <strong>and</strong> became nucleolar<br />
in sub-confluent cells. In the nucleolus, angiogenin bound to the upstream sequence <strong>of</strong><br />
45SrRNA promoter <strong>and</strong> increased 45SrRNA transcription. Angiogenin increased the antiapoptosis<br />
<strong>and</strong> cell proliferation <strong>of</strong> KSHV infected endothelial cells, <strong>and</strong> these activities<br />
were blocked by neomycin which blocked the nuclear translocation <strong>of</strong> angiogenin.<br />
Upregulation <strong>of</strong> angiogenin lead to an increased activation <strong>of</strong> urokinase plasminogen<br />
activator <strong>and</strong> generation <strong>of</strong> active plasmin from inactive plasminogen. Plasmin generation<br />
aided the migration <strong>of</strong> endothelial cells towards chemoattractant including angiogenin,<br />
<strong>and</strong> chemotaxis was prevented by the inhibition <strong>of</strong> angiogenin nuclear translocation.<br />
Tube formation <strong>of</strong> endothelial cells was significantly inhibited by treating infected cell<br />
supernatants with anti-angiogenin antibodies. Inhibition <strong>of</strong> nuclear translocation <strong>of</strong><br />
angiogenin also blocked VEGF-C expression. Collectively, these results suggest that KSHV<br />
induced angiogenin plays multiple roles during infection such as increase in 45SrRNA<br />
synthesis, proliferation, cell migration <strong>and</strong> angiogenesis, <strong>and</strong> blocking angiogenin could<br />
have a therapeutic value in treating KSHV infection <strong>and</strong> KS.<br />
Presenting author Email: bala.ch<strong>and</strong>ran@rosalindfranklin.edu<br />
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