HHV-8, angiogenesis and inflammation

Rosalind Franklin Univ Of Medicine & Sci, North Chicago IL

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Abstract

Inflammation is a complex host protective biological response of vascular tissues to various injurious stimuli including pathogenic microbes and an attempt to remove the stimuli and initiate the healing process. Unchecked chronic inflammation characterized by simultaneous destruction and healing of tissues can lead to a variety of diseases including cancer. Angiogenesis, a complex molecular events leading into formation of new blood vessels, is not only an essential component of inflammation and its resolution, but also tightly linked to chronic inflammation and cancer. However, there is a dearth of knowledge regarding the various molecules involved in angiogenesis and hence lack of an effective therapeutic control of angiogenesis. Human herpesvirus-8 (HHV-8) is etiologically associated with a chronic inflammation associated malignancy, namely Kaposi[unreadable]s Sarcoma (KS), as well as with two lymphoproliferative disorders. Our long term objectives are to decipher the molecular mechanisms of HHV-8 induced angiogenesis with a rationale that these studies will lead to the identification and development of novel therapeutic targets to control angiogenesis, inflammation, KS and other cancers. This proposal addresses the multi-functional Angiogenin (ANG), a key mediator of angiogenesis which is induced by HHV-8 during infection of endothelial cells and detected in KS tissues. HHV-8 induced ANG enters the nucleus and nucleolus, stimulated the infected endothelial cell 45S-rRNA gene transcription, proliferation and tube formation and extracellular matrix degradation. Cell proliferation, VEGF induction and tube formations were inhibited by blocking ANG nuclear translocation by neomycin and by treatment of infected cell supernatant with anti-angiogenin antibodies. ANG is induced in the latently infected endothelial cells as well as HHV-8 + B-lymphoma cells. ANG was induced by HHV-8 latent LANA-1 protein. ANG co-localized with LANA-1 in the nucleus of infected endothelial and B-lymphoma cells. We also discovered an anti-apoptotic role of ANG and ANG[unreadable]s interactions with p53. We hypothesize that HHV-8 has evolved to utilize the known as well as yet uncharacterized functions of ANG for its advantage. This hypothesis will be tested by three Specific Aims. 1. Decipher ANG interactions with LANA-1 and p53 proteins. 2. Decipher ANG[unreadable]s anti-apoptotic role in uninfected and HHV-8 infected cells and the potential mechanism of anti-apoptosis. 3. Decipher ANG[unreadable]s role in HHV-8 latency and evaluate the therapeutic potential of ANG inhibitors in controlling HHV-8 tumorigenesis. These studies have broad range of potential impact since deciphering the ability to block ANG and consequently eliminate HHV- 8 latent infection has the potential to use the angiogenin inhibitors as therapeutic agents to ameliorate HHV-8 associated angiogenesis, inflammation and malignancies.