Date of Award
Master of Science
Comparative and Experimental Medicine
Stephen A. Kania, Xuemin Xu
Cardiovascular disease, currently the leading cause of mortality throughout the developed countries, is mainly caused by atherosclerosis, which is recognized as a chronic inflammatory disease. Atherosclerotic plaques are characterized by accumulations of lipid in arterial walls together with infiltration of macrophages. These macrophages differentiate from monocytes which transform into foam cells through phagocytizing various forms of lipid, are believed to be the main component of early atherosclerotic lesions.
Lysophosphatidic acid (LPA), a potent bioactive lipid, regulates a broad range of cellular functions in various cell types. In our findings, LPA-induced macrophages may enhance the lipid uptake effect in both J774A.1-mouse macrophage cell lines and bone-marrow derived macrophages (BMDMs) in a time and dose dependent manner.
To date, LPA activated signaling pathways in macrophage and possible intracellular molecules mediating LPA-triggered foam cell formation wait to be explored. According to our results, we found: 1) LPA receptor 2 and 5 were predominantly expressed than other receptors in macrophages. 2) Protein Kinase D (PKD) underwent activation both on the Ser744/748 activation loop and auto phosphorylation site Ser916 from 2 minutes to 5 minutes upon the addition of LPA. 3) During the early period of LPA treatment, phospho-ERK, phospho-JNK and phospho-P38 all showed signs of short term inhibition - which indicates that MAPK activity had been transiently inhibited in macrophages by LPA. 4) NF-kappaB, a key transcriptional regulator in macrophages, showed no obvious patterns of activation in our investigation through observing that neither IKK nor IKB units were activated upon LPA induction. And this finding excludes the possibility that NF-kappaB pathway is involved in LPA-induced macrophage activation. 5) Our northern blot analysis demonstrated that, SR-B1 and CD36 – two scavenger receptors that are critical in lipid accumulation of macrophages – were up-regulated by LPA.
Collectively, all emerging data leads us to hypothesize that LPA, through its receptors to activate intracellular pathways, mediates downstream gene expression level, then expedites foam cell formation, which may contribute to atherosclerotic lesion formation.
Xu, Kan, "Mechanism of LPA-induced lipid uptake in macrophages. " Master's Thesis, University of Tennessee, 2013.