Atherosclerosis, considered a chronic inflammatory disease, is the underlying mechanism for several cardiovascular diseases. Hyperlipidemia is the number one risk factor for atherogenesis. Caspase-1 is an inflammatory caspase, which can be activated by the metabolic stresses through pathogen associated molecular patterns (PAMPs)-recognition receptors, (PRR) recognition and inflammasome assembly. Activated caspase-1 can initiate inflammation in multiple ways. Thus, regulating inflammasome components expression is essential to control caspase-1 activation and its subsequent inflammatory processes. I hypothesized that the readiness of inflammasome component expression for caspase-1 activation in tissues is an index for inflammation privilege. Endothelial cells (EC) which are the innermost layer of the vessel and are the critical gatekeeper for monocyte migration. The first step of atherogenesis is activation of ECs, which allows monocyte adhesion and migration into the sub-endothelial layer. I also hypothesized that caspase-1 can sense hyperlipidemia and regulate EC activation and inflammation during early atherogenesis. I first determined the expression profiles of inflammasome components, pro-inflammatory caspases and PRRs is different among tissues, and cardiovascular tissues express relative less PRRs via a database-mining method. According to the readiness of inflammasome components, tissues could be classified into three tiers. The first tier consists of tissues with constitutively expressed inflammasomes. The second tier of tissues includes potentially inducible expression of one inflammasome component. The third tier of tissues has inducible expression of at least two inflammasome components. This three-tier model can be applied to determine the inflammation privilege of tissues in response to pro-inflammatory stimuli. I also demonstrated that hyperlipidemia induced caspase-1 expression and activation in aorta along with the atherogenesis in apolipoprotein E (ApoE)-/- mice with high fat (HF) diet, experimentally. We then generated the ApoE-/-/Casp-1-/- double knockout mice, and found that the ApoE-/-/Casp-1-/- mice contained significantly less atherosclerotic lesion in aortic sinus and less cytokine and chemokine expression in aortic tissues compared with ApoE-/- mice. ApoE-/-/Casp-1-/- mice also had less CD11b+/F4/80- neutrophil and CD11b+/F4/80+ monocyte recruitments into aorta compared with ApoE-/- mice. However, the percentage of monocyte subsets in peryphery blood remained at the same level in between ApoE-/- mice and ApoE-/-/Casp-1-/- mice. I then proposed that perhaps the caspase-1 activation in vascular cells, in ECs played the essential role of controling monocyte migraion. My in vitro data demonstrated that oxidized low density lipoprotein (ox-LDL) and its componnents could induced caspase-1 activation in human aortic ECs (HAECs) through ROS pathway which then led to EC activation and pyroptotic cell death. Deficiency of caspase-1 in aortic EC attenuated hyperlipidemia induced EC activation and inflammtion. Mechanically, I found that caspase-1 deficiency accumulated an anti-atherogenic protein, Sirt-1 in the aorta. Collectively, our data suggested that caspase-1/inflammasome in ECs can sense hyperlipidemia, become activated, drive EC activation, and promote monocyte recruitment and early atherosclerosis. / Pharmacology
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/3889 |
| Date | January 2013 |
| Creators | Yin, Ying |
| Contributors | Yang, Xiao-Feng, Ashby, Barrie, Autieri, Michael V., Muniswamy, Madesh, Wang, Hong, 1956 September 19-, Song, Wenchao |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 176 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/3871, Theses and Dissertations |
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