Kaur, Jaspreet (2012) Role of chemerin, a novel adipochemokine, in the human microvascular endothelial cell (HMEC)-1 line. PhD thesis, University of Warwick.

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Abstract

Chemerin is a newly identified adipokine and exerts its functional effects by
binding to its natural GPCR, known as CMKLR1. Chemerin is highly expressed in
the adipose tissue and in lower levels in other body tissues; and is known to play an
important role in adipocyte differentiation and metabolism. Chemerin circulates at
the normal physiological concentrations of approximately 3-4nM in humans, and
circulating chemerin levels positively correlate with various facets of metabolic
abnormalities; such as insulin resistance, type 2 diabetes, high triglycerides,
hypertension, and associated risks of development of diseases of cardiovascular
system. Endothelial Cells (ECs) line the vasculature of the entire circulatory system
and form a direct contact with the bloodstream. In this project, the role of chemerin
in EC biology was proposed, and was studied in terms of activation of important
signalling Mitogen-activated Protein Kinases (MAPKs) including Extracellular
signal-regulated Kinase (ERK) 1/2, ERK5, p38, Stress-activated Protein Kinase/c-
Jun NH2-terminal Kinase (SAPK/JNK); and Akt/Protein Kinase B (PKB) and
Adenosine Monophosphate Protein Kinase (AMPK)-α in a time- and concentrationdependent
manners. These signalling kinases regulate the activity of different
transcription factors which then regulate the expression of different genes. Chemerin
increased the expression of Hypoxia-inducible Factor (HIF)-1α, a hypoxia-inducible
transcription factor which is known to regulate the Vascular Endothelial Growth
Factor (VEGF) gene expression. Interestingly, VEGF165, the most potent
angiogenic isoform of VEGF protein expression was down-regulated by chemerin in
a concentration-dependent manner; whereas, chemerin upregulated the protein
expression of VEGF165b, an opposite anti-angiogenic counterpart of VEGF165.
Chemerin mediated EC proliferation, migration and capillary tube formation; which
are the key processes implicated in the process of normal and pathological
angiogenesis. Chemerin altered the protein expression levels of Cell Adhesion
Molecules (CAMs) including E-selectin, ICAM-1 and VCAM-1 – increased the
activity of Nuclear Factor (NF)–kappa (κ) B pathway – and encouraged Endothelial-
Monocyte cell adhesion in a concentration-dependent manner. Nitric Oxide (NO),
not only keeps the vascular health in check by downregulating the expression levels
of adhesion molecules, but also acts as a potent vasodilator. Endothelial Nitric Oxide
Synthase (eNOS), an enzyme constitutively expressed in the endothelial cells
regulates the production of NO in the endothelium. Chemerin increased eNOS
activity by causing eNOS phosphorylation at Ser1177, and dephosphorylating at
Thr495 phosphorylation sites. Chemerin increased the protein expression of nonconstitutively
expressed enzyme, inducible Nitric Oxide Synthase (iNOS), which is
mainly induced during injury or inflammation and is known to produce 100- to
1000-times more NO compared to that of eNOS. However, interestingly, chemerin
failed to show any significant changes in the amounts of combined nitrite and nitrate
(NOx) levels in HMEC-1 cells; whereas, nitrite (NO2–) levels were decreased in a
concentration-dependent manner.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QP Physiology
Library of Congress Subject Headings (LCSH):	Vascular endothelial cells, Chemokines, Adipose tissues, Cytokines, Vascular endothelial growth factors, Protein kinases
Official Date:	May 2012
Dates:	Date Event May 2012 Submitted
Institution:	University of Warwick
Theses Department:	Warwick Medical School
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Randeva, Harpal S.
Sponsors:	General Charities of the City of Coventry
Extent:	xxviii, 320 leaves : illustrations.
Language:	eng

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