Year of Publication
Doctor of Philosophy (PhD)
Dr. Susan Smyth
Dr. Steve Estus
Coronary artery disease (CAD) is the leading cause of death in both men and women worldwide and is defined as a narrowing of the coronary arteries due to accumulation of atherosclerotic plaques. Genome-wide association studies have identified risk loci within the gene PPAP2B that confers increased risk of developing CAD. Evidence suggests these aforementioned SNPs are regulating PPAP2B expression in a cis-manner through the interruption of transcription factor binding sites. PPAP2B encodes the lipid phosphate phosphatase 3 enzyme that plays a key role in degrading bioactive lysophosphatidic acid (LPA). LPA has a plethora of effects on vascular tissue and is implicated in increasing inflammation and exacerbating the development of atherosclerotic lesions in mice. Interestingly, PPAP2B expression is increased in murine models of atherosclerosis and both global and smooth muscle cell-specific deletion increases the development of lesions compared to control mice. LPP3-deficient mice with increased atherosclerosis show significant increases in LPA accumulation in their proximal aorta as well as increased expression of inflammatory markers and positive staining for leukocyte marker CD68. Globally deficient mice also show substantial increases in ICAM-1 staining in their aortic root lesions relative to controls. Preliminary evidence also suggests that total LPA content, and specifically unsaturated LPA species, increase in the atherogenic LDL-C fractions of plasma in hyperlipidemic mice prone to developing atherosclerosis. Taken together, these data suggest that as CAD develops, LPA accumulates in atherosclerotic plaques, and the intrinsic mechanism of defense is to upregulate LPP3 through transcription factor- mediated effects on PPAP2B; however, individuals harboring the previously mentioned risk alleles are unable to increase PPAP2B expression and thus experience unchecked inflammation and exacerbated development of atherosclerosis.
Digital Object Identifier (DOI)
Mueller, Paul A., "PPAP2B EXPRESSION LIMITS LESION FORMATION IN MURINE MODELS OF ATHEROSCLEROSIS" (2016). Theses and Dissertations--Physiology. 28.