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J Pharmacol Ther Res 2017 Volume 1 Issue 2
November 02-03, 2017 Chicago, USA
4
th
International Congress on
International Conference and Exhibition on
Drug Discovery, Designing and Development
Biochemistry, Molecular Biology: R&D
&
Angiopoietin-like 4 as promoter of angiogenesis and vascular permeability
Silvia Montaner
University of Maryland, USA
A
ngiopoietin-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 post-
translational 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
intumorsappearstobeassociatedwithpoorprognosis
andpoor disease-free survival rates. Inour lab,weobserved 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.
e:
smontaner@umaryland.edu