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The effects of protease-activated receptor 2 on atherosclerosis

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2016, MS, University of Cincinnati, Allied Health Sciences: Nutrition.
Background: Cardiovascular disease (CVD), including heart attack, stroke, and heart failure, is the leading cause of morbidity and mortality worldwide. Atherosclerosis is a progressive disease of the arterial wall that is initiated by lipid retention, oxidation, and modification, which provoke inflammation, stenosis, and eventual thrombosis. Atherosclerotic plaques are highly procoagulant due to the presence of tissue factor (TF), the primary initiator of the coagulation cascade. Moreover, >97% of the total thrombotic potential in atherosclerotic plaques is attributable to TF. TF, when combined with factor VIIa (FVIIa), not only triggers clotting but also activates protease-activated receptor 2 (PAR-2). While TF deletion results in embryonic lethality and TF inhibition is not a feasible therapeutic option, targeting TF-induced PAR-2 signaling decreases smooth muscle cell migration and secretion of inflammatory cytokines, both of which are crucial to atherosclerotic initiation and progression. The role of PAR-2 in atherosclerosis has not yet been elucidated. Objective: To determine the effects of a high fat diet (HFD) on atherosclerotic plaque deposition and lipid profile of PAR-2 proficient (Par-2+/+) verses PAR-2 deficient (Par-2-/-) mice on a low-density lipoprotein deficient (Ldlr-/-) background. Methods: 8-12 week old male Ldlr-/- mice that were PAR2+/+ (n=20) or PAR2-/- (n=13) were fed a HFD for 12 weeks. Chimeric mice were generated in which male recipient Ldlr-/-/Par2+/+ or Ldlr-/-/Par2-/- mice (8-12 weeks old) were irradiated with a total of 11 Gy (2 doses of 550 rads 4 hours apart) using a Cs137 irradiator. Irradiated mice were re-populated with bone marrow harvested from Ldlr-/-/Par2+/+ (n = 17) or Ldlr-/-/Par2-/- (n = 16) donor mice via retro-orbitally injected cells to create four different chimeric groups. Body weight was measured at 8-12 weeks of age and at the time of sacrifice. Glucose tolerance and insulin sensitivity was assessed prior to high fat feeding. Upon sacrifice, plasma, heart, aorta, liver, epididymal fat, and retroperitoneal fat was collected. The liver, epididymal and retroperitoneal fat was weighed. Plasma was assessed for triglycerides, total cholesterol, high-density lipoprotein, and low-density lipoprotein. Quantification of atherosclerotic plaque within the aortic sinus was conducted via cryo-sectioning techniques. Results: Consumption of a high fat diet for 12 weeks trends towards (P<0.053) a decrease in atherosclerotic plaque development in PAR-2 deficient mice relative to PAR-2 proficient mice. Significant attenuation of weight gain (P<0.001), liver weight (P<0.001), epididymal (P<0.001) and retroperitoneal (P<0.001) fat was observed in Ldlr -/-PAR2-/- mice as well as PAR2-/-/BM-PAR2-/- mice (P<0.001, P<0.001, P<0.001, and P<0.001, respectively). Glucose tolerance and insulin sensitivity was not significantly different among Ldlr-/- /Par2 +/+ and Ldlr-/- PAR2-/- mice. No significant change in plasma triglycerides, cholesterol, HDL, or LDL was observed among any mouse groups. Conclusion: PAR-2 deficiency attenuated atherosclerotic burden and reduced weight gain and adipose deposition without affecting plasma lipids in a diet-induced atherogenic murine model.
Abigail Peairs, Ph.D. (Committee Chair)
Phillip Owens, Ph.D. (Committee Member)
Sarah Couch, Ph.D. (Committee Member)
61 p.

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Citations

  • Hall, D. (2016). The effects of protease-activated receptor 2 on atherosclerosis [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1459438552

    APA Style (7th edition)

  • Hall, David. The effects of protease-activated receptor 2 on atherosclerosis. 2016. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1459438552.

    MLA Style (8th edition)

  • Hall, David. "The effects of protease-activated receptor 2 on atherosclerosis." Master's thesis, University of Cincinnati, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1459438552

    Chicago Manual of Style (17th edition)