Cardiovascular diseases, including atherosclerosis, are the leading cause of death in the United States. Atherosclerotic lesions are formed by deposition of lipids in the intima of arteries. Upon exposure to oxidative stresses, low-density lipoprotein (LDL) is converted to highly atherogenic oxidized LDL (ox-LDL) particles, contributing to disease development and progression. Advanced disease stages may result in calcification of lesions. This calcification process is important, as it has been shown to be associated with stable plaques that are less prone to rupture. Calcification is present in lipid rich domains of lesions, however neither the composition of the mineralized calcium deposits nor its relationship to lipid peroxidation or the lipid rich atherosclerotic core has previously been identified. This study provides evidence that the lipid peroxide derived dicarboxylic acid (DCA), azelaic acid (AzA) induces calcification in smooth muscle cells, thereby providing the link between calcification and overall plaque burden, and association of calcification with the lipophilic region of the lesion. The potential of lipid peroxide-derived lipophilic DCAs to promote calcification upon exposure to vascular smooth muscle cells was tested. 13-hydroperoxylinoleic acid (HPODE) treatment resulted in the cellular conversion to 9-oxononanoic acid (ONA) and AzA as determined by mass spectrometry analysis. Delivery of AzA via lysophosphatidylcholine (Lyso-PtdCho) micelles induced calcification of human aortic smooth muscle cells (HASMC). AzA was identified in calcified human and mouse atherosclerotic plaques. Calcification of HASMC due to AzA treatment resulted in a less inflammatory and oxidative environment as indicated by genetic expression. These results demonstrate that DCAs may contribute to atherosclerotic calcification thus accounting for the latter's relationship to plaque burden and association with lipids. This study also challenges the dogma that arterial calcification represents the deposition of calcium phosphate and has implications with the development of new therapeutic strategies in treating late stage atherosclerosis.
Doctor of Philosophy (Ph.D.)
College of Medicine
Burnett School of Biomedical Sciences
Length of Campus-only Access
Doctoral Dissertation (Campus-only Access)
Riad, Aladdin, "Role of Lipid Peroxide Derived Dicarboxylic Acids in Atherosclerotic Calcification" (2018). Electronic Theses and Dissertations, 2004-2019. 6226.