Atherosclerosis

Jarr and colleagues show that statins augment efferocytosis by inhibiting the nuclear translocation of NF-κB1 p50 and suppressing the expression of the key ‘don’t-eat-me’ molecule CD47, which in part explains the pleiotropic effects of statins and provides a basis for future translational efforts.

Sun and Li propose and validate a model for cholesterol engagement and transport via the ATP-binding cassette transporter ABCA1, via generating and comparing high-resolution cryo-EM structures of three distinct states of the transporter: with and without ATP and a mutant form unable to export cholesterol that is relevant to human pathology

Zong and colleagues reveal a critical role for the ion channel TRPM2 in macrophages through mediating reactive oxygen species production, inflammasome activation, oxidized LDL uptake and subsequently inflammatory responses, which they show is mediated by CD36 activity, thereby establishing a mutually regulating and positive feedback mechanism between CD36 and TRPM2 in atherogenesis.

Cheng et al. show that smooth muscle cell (SMC)-specific deletion of Smad3 influences the fate of de-differentiated SMCs in atherosclerotic plaques in vivo, promoting both a pro-remodeling SMC transition phenotype and expansion of the SMC-derived chondromyocyte population. These cellular changes are associated with increased outward remodeling and plaque calcification.

Atherosclerosis is accompanied by an autoimmune response that includes CD4 T cells recognizing epitopes in apolipoprotein B (APOB). Saigusa et al. analyzed the transcriptomes and T cell receptors of APOB-specific CD4 T cells by single-cell RNA sequencing using MHC-II tetramers in women with atherosclerosis, and showed that APOB-specific regulatory T cells switch to a more memory-like phenotype in atherosclerosis.

Using various mouse models, human plaque data and isolated B cells combined with state-of-the-art imaging and transcriptomic analysis, the authors show that the G-protein-coupled orphan receptor GPR55 regulates B cell activation and plasma cell differentiation during hypercholesterolemia, which crucially affects atherosclerosis.

Mokry et al. performed bulk RNA sequencing of 654 advanced human carotid plaques from the Athero-Express biobank and 162 coronary samples, and they show that unsupervised clustering defines plaque types corresponding to different cell compositions and clinical presentations. Circulating biomarkers can be potentially used to mark the different transcriptomic-defined plaque phenotypes.

Mauersberger and colleagues show that loss of function of soluble guanylyl cyclase (sGC) in platelets increases plaque burden in atherosclerosis-prone Ldlr^−/− mice by increasing leukocyte adhesion to atherosclerotic plaques. While mouse platelets lacking sGC and human platelets from carriers of GUCY1A1 risk alleles showed reduced secretion of angiopoietin-1, pharmacological sGC stimulation increased platelet angiopoietin-1 release in vitro and reduced leukocyte recruitment and atherosclerotic plaque formation in vivo, suggesting sGC as a potential therapeutic target for the treatment and prevention of atherosclerosis.

Zekavat, Matesanz, Viana-Huete et al. show an increased risk of peripheral artery disease and atherosclerosis in different vascular beds in patients with clonal hematopoiesis of indeterminate potential (CHIP) caused by mutations in DNA damage repair genes, such as TP53. Validations in a mouse model support the causal contribution of TP53-mutant CHIP to atherosclerosis.

Depuydt and Schaftenaar et al. profile the T cell clonality in patients with atherosclerosis by performing single-cell T cell receptor sequencing on carotid artery plaques and matched peripheral blood mononuclear cell samples. The analyses showed plaque-specific clonal expansion in effector CD4⁺ T cells, expressing genes indicative of exposure to activating antigens, thus suggesting that atherosclerosis has an autoimmune component driven by autoreactive CD4⁺ T cells.

Wang et al. profiled T cells in atherosclerotic plaques, artery tertiary lymphoid organs, and lymph nodes in mice with advanced atherosclerosis by single-cell RNA sequencing paired with T cell antigen receptor sequencing and observed complex patterns of deteriorating peripheral T cell tolerance. Signs of CD8⁺ tolerance dysfunction were found also in human plaques transcriptomic data, indicating that atherosclerosis can be considered as a bona fide T cell autoimmune disease.

Anisimov, Fang et al. report that in humans, genetic variants associated with higher TIE2 expression are predicted to confer a reduced risk of CAD; in mice, Tie2 expression in endothelial cells is atheroprotective, and in a subset of aortic fibroblasts, anti-inflammatory.

The bone morphogenetic protein (BMP) 9/10 receptor, ALK1, was recently shown to mediate LDL entry and transcytosis in endothelial cells. Here, Lee et al. show that genetic ablation of arterial endothelial ALK1 in mice limits atherosclerosis without affecting cholesterol or triglyceride levels and that a monoclonal antibody binding ALK1 efficiently blocks LDL transcytosis, but not BMP9 signaling, leading to a reduction in plaque burden.

Liu et al. show that statin enhances cardiovascular disease protection through epigenetic modulation of YAP–SOX9 signaling, improving endothelial function and offering new therapeutic strategies.

Amadori et al. show that plasma from patients with atherosclerosis triggers unique inflammatory transcriptomic and signaling signatures in peripheral blood mononuclear cells, which were used for selecting drugs that may be repurposed for the treatment of atherosclerosis.

Liu et al. report that the IL-6R antibody reduces the atherosclerosis promoted by Tet2 clonal hematopoiesis (CH) via reversal of increased macrophage colony-stimulating factor 1 receptor expression and suggests blocking IL-6 signaling as a potential therapy for CH-driven cardiovascular disease.

Alan Tall and Jose Fuster review the latest advances in our knowledge of the function of clonal hematopoiesis in cardiovascular disease and discuss the translation of this knowledge into therapeutics.

Libby and Tokgözoğlu discuss the management of atherogenic lipoproteins, notably low-density lipoprotein, with an emphasis on the role of strategies that target PCSK9.

Ziad Mallat and Christoph Binder discuss the current knowledge of the adaptive immune response in the immuno-cardiovascular unit, in health and in atherosclerotic disease.