PROTEASE-ACTIVATED RECEPTOR SIGNALING IN CELLULAR DIFFERENTIATION FOLLOWING VASCULAR AND HEPATIC INJURY.
Protease-activated receptors (PARs) are a family of G protein coupled receptors whose
aberrant activation influences a variety of disease states including cardiovascular
disease, liver fibrosis, arthritis, sepsis, and cancer. This thesis focuses on the
pathologic role of PAR1 and PAR2 signaling following vascular and hepatic injury.
Atherothrombotic disease remains the leading cause... read moreof death in the United States, Europe
and Western nations. PAR1, also known as the high-affinity thrombin receptor, has
emerged as a new drug target in patients undergoing percutaneous coronary intervention
(PCI) for treatment of atherothrombotic disease. However, studies with direct thrombin
inhibitors have not demonstrated a beneficial effect in preventing restenosis of culprit
lesions post-PCI. Here, we identify matrix metalloprotease-1 (MMP-1) as a non-canonical
PAR1 agonist that specifically stimulates smooth muscle cell (SMC) de-differentiation,
hyperplasia and migration, resulting in phenotypic alterations that favor a restenotic
program. In contrast, thrombin-PAR1 signaling promotes a differentiated, contractile
phenotype in vascular SMCs. Unlike thrombin blockade, inhibition of MMP1-activity leads
to marked suppression of restenosis in mouse models of arterial wire-injury. These
findings suggest a MMP1-driven phenotypic switch via PAR1 with therapeutic implications
for suppressing post-injury restenosis. Non-alcoholic fatty liver disease (NAFLD), and
the more severe non-alcoholic steatohepatitis (NASH), are liver manifestations of
obesity and insulin resistance. The prevalence of NAFLD in the general population is
estimated between 10-46%. PAR2-driven activation and differentiation of hepatic stellate
cells has been implicated in the pathogenesis of NAFLD and NASH. Using a
cell-penetrating PAR2 antagonist pepducin, we demonstrate decreased steatosis and
hepatic inflammation in animal models of NASH, providing critical evidence for the use
of PAR2 inhibitors in the treatment of
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Genetics.
Advisors: Athan Kuliopulos, and Gordon Huggins.
Committee: Janis Lem, and Grace Gill.
Keywords: Cellular biology, and Medicine.read less