Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Pharmacology and Physiology, 2013.
Cardiovascular diseases (CVD) are among the leading causes for
morbidity and mortality in the western world. Examples of CVD include
congestive heart failure, coronary artery disease and myocardial
infarction, hypertension and stroke. Common to all these diseases is
atherosclerosis, a pathologic process of arteries characterized by
inflammation, lipid accumulation, arterial stenosis, formation of cholesterol
plaques and ultimately plaque rupture. Today it has become clear that a
pathophysiologic mechanism that promotes atherosclerosis is endothelial
cell (EC) dysfunction. EC were originally thought to be merely passive
lining of blood vessels, but over the last 35 years it has become clear that
EC play critical role in all phases of atherosclerosis.
To date, multiple factors were shown to be contributors for the
initiation and propagation of CVD (e.g. altered angiotensin II signaling and
endothelial injury/dysfunction). An underlying mechanism for those risk
factors is increased oxidative stress and altered reduction-oxidation
signaling.
Previous studies from the Berk lab demonstrated that in intact
vessels an important protein regulated reduction-oxidation signaling,
thioredoxin-interacting protein (TXNIP). TXNIP, via inhibition of an antixi
oxidant protein thioredoxin (TRX), promotes oxidative stress, endothelial
inflammation and apoptosis. Data from other labs demonstrate a critical
role for TXNIP in regulation of multiple organs, such as blood vessels,
heart and liver. Interestingly, not all of these effects were related to
TXNIP’s ability to inhibit TRX activity. Therefore, TXNIP was proposed to
act as a multi-functional protein to orchestrate cellular response and
regulate homeostasis.
Recently, TXNIP was described as a member of the α-arrestin
family of proteins that were shown to act as scaffold proteins to regulate
the subcellular localization and function of interacting proteins. Therefore,
my focus was to investigate TXNIP function as an α-arrestin protein that
mediates intracellular signaling in EC.
The data presented here describes TXNIP function in the regulation
of plasma membrane signaling events. Specifically, two novel functions
were discovered. First, TXNIP is a regulator of VEGFR2 activation, in a
PARP1-dependent mechanism. Second, it acts as a blood flow
mechanosensor to regulate EC stress fibers, by inhibiting Src signaling.
Future work will investigate the role of TXNIP in angiogenesis, vasculature
development and atherosclerosis.
