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Background: Atherosclerosis progression is modulated by interactions with the adaptive immune system. Humoral immunity can help protect against atherosclerosis formation; however, the existence, origin, and function of putative atherogenic antibodies are controversial. How such atherosclerosis-promoting antibodies could affect the specific composition and stability of plaques, as well as the vasculature generally, remains unknown., Methods: We addressed the overall contribution of antibodies to atherosclerosis plaque formation, composition, and stability in vivo (1) with mice that displayed a general loss of antibodies, (2) with mice that had selectively ablated germinal center-derived IgG production, or (3) through interruption of T-B-cell interactions and further studied the effects of antibody deficiency on the aorta by transcriptomics., Results: Here, we demonstrate that atherosclerosis-prone mice with attenuated plasma cell function manifest reduced plaque burden, indicating that antibodies promote atherosclerotic lesion size. However, the composition of the plaque was altered in antibody-deficient mice, with an increase in lipid content and decreases in smooth muscle cells and macrophages, resulting in an experimentally validated vulnerable plaque phenotype. Furthermore, IgG antibodies enhanced smooth muscle cell proliferation in vitro in an Fc receptor-dependent manner, and antibody-deficient mice had decreased neointimal hyperplasia formation in vivo. These IgG antibodies were shown to be derived from germinal centers, and mice genetically deficient for germinal center formation had strongly reduced atherosclerosis plaque formation. mRNA sequencing of aortas revealed that antibodies are required for the sufficient expression of multiple signal-induced and growth-promoting transcription factors and that aortas undergo large-scale metabolic reprograming in their absence. Using an elastase model, we demonstrated that absence of IgG results in an increased severity of aneurysm formation., Conclusions: We propose that germinal center-derived IgG antibodies promote the size and stability of atherosclerosis plaques, through promoting arterial smooth muscle cell proliferation and maintaining the molecular identity of the aorta. These results could have implications for therapies that target B cells or B-T-cell interactions because the loss of humoral immunity leads to a smaller but less stable plaque phenotype.

Background: The majority of the human genome comprises noncoding sequences, which are in part transcribed as long noncoding RNAs (lncRNAs). lncRNAs exhibit multiple functions, including the epigenetic control of gene expression. In this study, the effect of the lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) on atherosclerosis was examined., Methods: The effect of MALAT1 on atherosclerosis was determined in apolipoprotein E-deficient (Apoe - /- ) MALAT1-deficient (Malat1 -/- ) mice that were fed with a high-fat diet and by studying the regulation of MALAT1 in human plaques., Results: Apoe -/- Malat1 -/- mice that were fed a high-fat diet showed increased plaque size and infiltration of inflammatory CD45 + cells compared with Apoe -/- Malat1 +/+ control mice. Bone marrow transplantation of Apoe -/- Malat1 -/- bone marrow cells in Apoe -/- Malat1 +/+ mice enhanced atherosclerotic lesion formation, which suggests that hematopoietic cells mediate the proatherosclerotic phenotype. Indeed, bone marrow cells isolated from Malat1 -/- mice showed increased adhesion to endothelial cells and elevated levels of proinflammatory mediators. Moreover, myeloid cells of Malat1 -/- mice displayed enhanced adhesion to atherosclerotic arteries in vivo. The anti-inflammatory effects of MALAT1 were attributed in part to reduction of the microRNA miR-503. MALAT1 expression was further significantly decreased in human plaques compared with normal arteries and was lower in symptomatic versus asymptomatic patients. Lower levels of MALAT1 in human plaques were associated with a worse prognosis., Conclusions: Reduced levels of MALAT1 augment atherosclerotic lesion formation in mice and are associated with human atherosclerotic disease. The proatherosclerotic effects observed in Malat1 -/- mice were mainly caused by enhanced accumulation of hematopoietic cells.