Abstract 13829: Low Density Lipoprotein Receptor on the Immune Cells Influence the Atherosclerosis Progression in C57bl/6 Mice

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Introduction: Atherosclerosis is the leading cause of cardiovascular diseases (CVDs). Over the past three decades, the clinical focus has been reducing plasma lipids and other traditional risk factors to reduce cardiovascular mortality. More recently, the CANTOS trial showed that inflammation is a significant additional risk factor for CVDs. Regulatory T cells (Tregs) are well known to protect the aorta from the inflammatory burden, but clinically how to induce these cells is not known. Hypothesis: LDLr is expressed on various immune cells, including Tregs. Recently, our lab found that modulating the lipid metabolism through LDLr in Tregs protects mice from colitis. Collectively, our data illustrate that LDLr plays an essential role in T cell homeostasis and function that may impact atherosclerosis progression. Therefore, our goal in this study is to test whether the absence of LDLr in immune cells alters the development of atherosclerosis. Methods: We used C57BL/6J male mice, which were lethally irradiated and transplanted with either LDLr-/- or WT bone marrow (BMT). To induce atherosclerosis, we blocked hepatic triglyceride clearance (antisense oligonucleotides) and fed mice with a high-fat diet for 12 weeks. We then collected blood and aorta to assess the extent of atherosclerosis. Results: Mice transplanted with LDLr-/- bone marrow have a lower percentage of T lymphocytes such as Th1 cells, Th1/Th2 hybrid cells, and pro-inflammatory M1 macrophages in the aorta compared to WT BMT aorta. Conversely, LDLr-/- BMT mice had a lower percentage of total Tregs but a significantly higher percentage of Tregs expressing the anti-inflammatory cytokine IL-10 and a lower percentage of Tregs co-expressing the pro-inflammatory marker T-bet compared to WT BMT aorta. Also, LDLr-/- BMT mice exhibited a 2-fold increase in plasma IL-10 compared to WT BMT plasma. Conclusion: Altogether, the current study's finding suggests that the loss of the LDLr in the immune compartment (bone marrow) can induce a significant change in the aortic immune cells and may be a future target for augmenting the protective Tregs population in CVD patients.

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