bioRxiv2023
BackgroundThromboembolic events secondary to rupture or erosion of advanced atherosclerotic lesions are the leading cause of death in the world. The most common and effective means to reduce these major adverse cardiovascular events (MACE), including myocardial infarction (MI) and stroke, is aggressive lipid lowering via a combination of drugs and dietary modifications. However, little is known regarding the effects of reducing dietary lipids on the composition and stability of advanced atherosclerotic lesions, the mechanisms that regulate these processes, and what therapeutic approaches might augment the benefits of lipid lowering. MethodsSmooth muscle cell (SMC)-lineage tracing Apoe-/- mice were fed a Western diet (WD) for 18 weeks and then switched to a low-fat chow diet for 12 weeks. We assessed lesion size and remodeling indices, as well as the cellular composition of aortic and brachiocephalic artery (BCA) lesions, indices of plaque stability, overall plaque burden, and phenotypic transitions of SMC, and other lesion cells by SMC-lineage tracing combined with scRNA-seq, CyTOF, and immunostaining plus high resolution confocal microscopic z-stack analysis. In addition, to determine if treatment with a potent inhibitor of inflammation could augment the benefits of chow diet-induced reductions in LDL-cholesterol, SMC-lineage tracing Apoe-/- mice were fed a WD for 18 weeks and then chow diet for 12 weeks prior to treating them with an IL-1{beta} or control antibody (Ab) for 8-weeks. ResultsLipid-lowering by switching Apoe-/- mice from a WD to a chow diet reduced LDL-cholesterol levels by 70% and resulted in multiple beneficial effects including reduced overall aortic plaque burden as well as reduced intraplaque hemorrhage and necrotic core area. However, contrary to expectations, IL-1{beta} Ab treatment resulted in multiple detrimental changes including increased plaque burden, BCA lesion size, as well as increased cholesterol crystal accumulation, intra-plaque hemorrhage, necrotic core area, and senescence as compared to IgG control Ab treated mice. Furthermore, IL-1{beta} Ab treatment upregulated neutrophil degranulation pathways but down-regulated SMC extracellular matrix pathways likely important for the protective fibrous cap. ConclusionsTaken together, IL-1{beta} appears to be required for chow diet-induced reductions in plaque burden and increases in multiple indices of plaque stability. Clinical PerspectiveAlthough one must be cautious in extrapolating results of mouse studies to humans, the current and our previous studies (Gomez et al. 2018 Nature Medicine) suggest that efforts to identify anti-inflammatory therapies for treating patients with advanced atherosclerosis should consider the possibility that inhibiting a given cytokine may have a mixture of beneficial and detrimental effects that vary between individuals. What is New?In a mouse model of advanced atherosclerosis followed by diet-induced reductions in cholesterol, IL-1{beta} inhibition unexpectedly had multiple detrimental effects including increasing overall plaque burden and decreasing various indices of plaque stability, as well as markedly increasing the number of senescent cells, and cholesterol crystal accumulation in lesions as compared to IgG control Ab treated mice. What are the clinical Implications?Results suggest that some anti-inflammatory therapies may have limited efficacy for treating patients with advanced atherosclerosis because such therapies inhibit not only detrimental pro-inflammatory responses, but also evolutionarily conserved beneficial inflammatory processes, which play a critical role in resistance to pathogenic microorganisms, in tissue repair following injury, and resolution of inflammation. We propose that the latter includes clearance of senescent cells and cholesterol from advanced atherosclerotic lesions induced by dietary-induced lipid lowering.