An early event in atherogenesis is accumulation of LDL in the artery wall in association with extracellular matrix (ECM). LDL sequestered on ECM is prone to oxidation and other modifications. LDL may also be modified within the circulation. The central hypotheses of this proposal are: 1. Apolipoprotein B stabilizes the LDL surface; thus conditions which lower the surface concentration of apo B (e.g., certain hyperlipemias where LDL radius increases without a concommitant increase in protein) or disrupt the structure and integrity of apo B (e.g., oxidation) can destabilize LDL. 2. The instability of LDL can lead to: a. Homogeneous fusion of LDL. Such fusion has been reported to lead to foam cell formation. b. Heterogeneous fusion of LDL with hydrophobic sites, such as collagens and elastins of artery wall ECM.
The specific aims of this proposal are to examine both thermodynamic and kinetic aspects of LDL fusion. In particular: 1. To test the hypothesis that hyperlipemic and oxidized LDL are more prone to homogeneous fusion than are normal LDL. 2. To test the contribution of increased interfacial tension and altered surface charge to the process of homogeneous fusion. 3. To determine whether adsorption of amphiphilic beta strand peptides to hyperlipemic and oxidized LDL inhibits homogeneous fusion. 4. To test the hypothesis that hyperlipemic and oxidized LDL are more prone to heterogeneous fusion to ECM proteins than are normal LDL. Collagens will be used as the prototype of ECM proteins, these studies will then be extended to elastin.
| Tsao, R; Jones, S A; Giddens, D P et al. (1995) An automated three-dimensional particle tracking technique for the study of modeled arterial flow fields. J Biomech Eng 117:211-8 |
