Journal of Pharmacology and Therapeutic Research

Angiopoietin-like 4 as promoter of angiogenesis and vascular permeability

4^th International Congress on Drug Discovery, Designing and Development & International Conference and Exhibition on Biochemistry, Molecular Biology: R&D
November 02-03, 2017 Chicago, USA

Silvia Montaner

University of Maryland, USA

Scientific Tracks Abstracts : J Pharmacol Ther Res

Abstract:

Angiopoietin-like 4 (ANGPTL4), a member of the ANGPTL family, is involved in many pathological disorders, including cardiac and lung diseases, cancer, retinal diseases, diabetes, atherosclerosis and nephrotic syndrome. This cytokine is a circulating multifunctional protein, which undergoes posttranslational modifications (glycosylation) and subsequent proteolytic processing by membrane proprotein convertases, upon secretion of the full-length gene product. ANGPTL4 N-terminal domain (nANGPTL4) acts as an adipokine, inhibiting lipoprotein lipase (LPL) and causing hydrolysis of circulating triglycerides (TG) into free fatty acids, under conditions of fasting and exercise. Alternatively, ANGPTL4 C-terminal domain (cANGPTL4) has an important role in anoikis resistance, altered redox regulation, tumorigenesis, and angiogenesis. Compelling evidence suggests a role of cANGPTL4 in solid tumors, including melanoma, breast carcinoma, hepatocellular carcinoma, renal cell carcinoma and colorectal cancer. The overexpression of ANGPTL4 in tumors appears to be associated with poor prognosis and poor disease-free survival rates. In our lab, we observed that ANGPTL4 is a pro-angiogenic factor in Kaposi’s sarcoma (KS), a vascular tumor caused by infection with human herpesvirus 8 or KS-associated herpesvirus (HHV-8/KSHV), and a common type of oral cancer in immunocompromised individuals. We observed upregulation of ANGPTL4 in both oral KS lesions and KS animal models because of the expression of the HHV8/KSHV G protein-coupled receptor (vGPCR), a constitutively-active viral GPCR homolog to CXCR2. The mechanism by which vGPCR induces ANGPTL4 gene expression includes the activation of Hypoxia Inducible Factor 1 (HIF1). Interestingly, we found that vGPCR-induced ANGPTL4 upregulation promotes angiogenesis in KS by the potent induction of endothelial cell migration. We also found that ANGPTL4 promotes vessel hyperpermeability, disrupting both adherens and tight endothelial junctions, an effect that contributes to the profuse edema seen in this tumor. Our results suggest that ANGPTL4 may be a novel therapeutic target for KS and other disorders associated with pathologic angiogenesis and vascular hyperpermeability.

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