PROTEASE-ACTIVATED RECEPTOR SIGNALING IN CELLULAR DIFFERENTIATION FOLLOWING VASCULAR AND HEPATIC INJURY.
Austin, Karyn.
2013
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Abstract: 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 of d... read moreeath 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 NAFLD/NASH.
Thesis (Ph.D.)--Tufts University, 2013.
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 - ID:
- 2n49td04r
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