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