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Dissertation
Physiological enzymatic regulation of low density lipoprotein aggregation and its effect on atherogenesis
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2010
DOI:
https://doi.org/10.17918/etd-3369
Abstract
Atherosclerosis is a cardiovascular disease involving maladaptive accumulation of lipids, extracellular matrix, and cells in arterial intima, which is initiated by subendothelial retention of atherogenic lipoproteins; primarily low density lipoprotein (LDL). Though drugs that lower plasma LDL concentration have been successful at reducing risk of cardiovascular disease, it is still a leading cause of death, as cardiovascular events can still occur at lower LDL concentrations. Consequently, complimentary therapeutic strategies are necessary that would impact the fate of LDL even at lower concentrations, by interfering with crucial steps of atherogenesis including: 1. Subendothelial LDL retention (irreversible transport of LDL from lumen to intima); 2. Enzymatic modification and subsequent aggregation of LDL retained in the intima; and 3. Uptake of this modified and aggregated LDL by macrophages in the intima. To accomplish these goals we focused on studying the atherogenic roles of lipoprotein lipase (LpL), which bridges LDL to smooth muscle cell (SMC) extracellular matrix, andsphingomyelinase (Smase), which causes LDL aggregation and fusion. These enzymes are both well characterized, but the specific mechanisms of their involvement in atherogenesis are not completely clear. Understanding their precise roles could result in the development of novel therapeutics. The results of our study show that: 1. LpL is selfsufficient to induce LDL aggregation; 2. LDL aggregate size is proportional to ceramide concentration and is independent of Smase concentration, demonstrating a physiologically relevant example of the hydrophobic effect in the LDL phospholipid monolayer; 3. Smase-treatment of LpL-induced LDL aggregates does not enhance aggregation and results in a ~3-fold inhibition of ceramide production; 4. LDL aggregation kinetics resulting from simultaneous addition of LpL and Smase show maxima followed by decreases in aggregate size; 5. Neither ceramide generation nor LDL aggregation, induced by LpL and Smase treatment, were affected by the presence of SMC extracellular matrix; and 6. LDL aggregates formed by vortex-mixing or by Smase treatment showed maximal uptake by macrophages at intermediate aggregate radii, consistent with mathematical models, describing competition between aggregate surfacearea and volume. The mechanisms of LDL modification, aggregation, and uptake provide specific points of intervention to design novel effective antiatherogenic therapeutics.
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Details
- Title
- Physiological enzymatic regulation of low density lipoprotein aggregation and its effect on atherogenesis
- Creators
- Michael Jared Walters - DU
- Contributors
- Steven P. Wrenn (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Chemical (and Biological) Engineering [Historical]; College of Engineering (1970-2026); Drexel University
- Other Identifier
- 3369; 991014632258704721