dc.contributor.author |
Kazezian, Zepur Hagop. |
dc.date.accessioned |
2013-10-02T09:24:07Z |
dc.date.available |
2013-10-02T09:24:07Z |
dc.date.issued |
2012 |
dc.identifier.uri |
http://hdl.handle.net/10938/9682 |
dc.description |
Advisor: Dr. Ayad A. Jaffa, Professor, Biochemistry and Molecular Genetics--Committee Members : Dr. Fuad Ziyadeh, Professor, Biochemistry and Molecular Genetics; Dr. Aida Habib-Abdul Karim, Professor, Biochemistry and Molecular Genetics; Dr. Nadine Darwiche, Professor, Biochemistry and Molecular Genetics; Dr. Asad Zeidan, Assistant Professor, Anatomy, Cell Biology and Physiology. |
dc.description |
Thesis (M.Sc)--American University of Beirut, Department of Biochemistry and Molecular Genetics, Faculty of Medicine . |
dc.description |
Includes bibliographical references (leaves 54-65) |
dc.description.abstract |
Background: Atherosclerosis is a silent chronic inflammatory disease that is a major cause of death worldwide. Due to the injury of endothelial cells aligning the aorta, the blood contents such as white blood cells, cytokines, growth factors and lipids interact directly with the smooth muscle cells of the vessel wall leading to vascular remodeling and lesion formation. Reactive oxygen species (ROS) generation in vascular smooth muscle cells activates signaling pathways, which contribute to vascular remodeling. Hypothesis: Mechanisms through which atherosclerosis mediate its effect on vessel walls are not well defined; however, there are many factors that contribute to the vascular remodeling like inflammatory mediators, cytokines and growth factors. Hence, we hypothesized that kallikrein-kinin system (KKS) specially bradykinin (BK) has a role in vascular remodeling via ROS generation, crosstalk with Sphingosine-1- Phosphate receptors (S1PR) s, and inducing the signaling pathways. Results: When BK acts directly on the smooth muscle cells leading to the synthesis of ROS; ROS in turn activate signaling pathways like mitogen-activated protein kinases (MAPK)s and Phosphatidylinositol-3 kinase (PI3K). This was confirmed by using Nacetylcysteine (NAC), a scavenger of ROS that led to a significant decrease in extracellular signal-regulated kinase (ERK1-2) and AKT. We also discovered that there is a crosstalk between bradykinin and S1PRs via sphingosine kinase 1 (SphK1) due to ROS generation by BK. On the other hand, when we used NAC, the ROS generation and the downstream signaling pathways of bradykinin 2 receptor (B2R) were inhibited, also CTFG, Fn and (SphK1) gene expression was decreased. Besides, we verified that S1P activates MAPK and PI3K pathways by increasing ERK1-2 and AKT respectively, which leads to proliferation and migration of smooth muscle cells. S1P also increases CTGF and Fn production, which leads to the production of extracellular matrix (ECM) particularly by S1PR1. Conclusion: Conclusion: The results |
dc.format.extent |
xii, 65 leaves : ill. + 1 CD-ROM. |
dc.language.iso |
eng |
dc.relation.ispartof |
Theses, Dissertations, and Projects |
dc.subject.classification |
W 4 K238e 2012 |
dc.subject.lcsh |
Kallikrein-Kinin-System. |
dc.subject.lcsh |
Dissertations, Academic. |
dc.subject.lcsh |
Atherosclerosis. |
dc.subject.lcsh |
Bradykinin. |
dc.subject.lcsh |
Kallikreins. |
dc.subject.lcsh |
Sphingosine. |
dc.title |
The effect of reactive oxygen species generation on the crosstalk between Bradykinin and Sphingosine-1-phosphate receptors in vascular smooth muscle cells |
dc.type |
Thesis |
dc.contributor.department |
American University of Beirut. Faculty of Medicine. Department of Biochemistry and Molecular Genetics. |