THE ROLE OF SMOOTH MUSCLE CELL NOGO-B IN ATHEROSCLEROSIS PLAQUE DEVELOPMENT AND STABILITY

Cardiovascular diseases are the leading causes of death in the world, with atherosclerosis playing a crucial role in many of these conditions. Atherosclerosis develops over decades as fatty deposits and debris accumulate to form plaques on the arterial intima. When these plaques progress severely, they can lead to myocardial infarction or stroke. Although the development and progression of atherosclerosis are not fully understood, recent findings indicate that plaque stability is significantly influenced by the phenotypic switch of vascular smooth muscle cells (VSMCs). A member of the reticulon family of proteins, Nogo-B, is highly expressed in SMCs, endothelial cells, and macrophages. Previous data in the lab with global Nogo-B deletion exacerbated atherogenesis by increasing lesion area and necrotic core size while decreasing cap thickness and collagen deposition. Our previous studies also suggest that Nogo-B attenuates growth factor-induced SMC proliferation and neointimal formation after vascular injury. This study aims to elucidate the role of SMC-specific Nogo-B in plaque development and stability, as well as determine its role in SMC phenotypic switching in a murine model of atherosclerosis. A murine atherosclerosis model was generated by specifically deleting Nogo-B in SMCs of ApoE-/- background mice with a Cre-recombinase system (Nogo-BiSMCKO) and feeding a high-fat diet with 1.25% cholesterol (HFD) for 14 weeks. SMC-Nogo-B loss demonstrated a decreased necrotic core, minimized lesion size, and increased collagen content in aortic root lesions, all of which are indices of a more stable plaque phenotype. Nogo-B deletion in cultured SMCs stimulated with β-CD cholesterol (20μg/ml) was performed to investigate phenotypic modulation and trans-differentiation in vitro. After cholesterol stimulation, expression of smooth muscle contractile genes was maintained in cells deficient in Nogo-B while decreasing in WT cells. Furthermore, SMCs deficient in Nogo-B had decreased cholesterol uptake. Mechanistically, our results show that Nogo-B modulates SMC plasticity through transcription factor Krüppel-like factor 4 (KLF4). In summary, SMC-specific Nogo-B deficiency attenuates atherogenesis and promotes stable plaque phenotypes. SMC-specific Nogo-B deficiency may aid in the therapeutic intervention of atherosclerosis by improving plaque stability and patient prognosis.