| 1. |
- Dib, Lea, et al.
(författare)
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Lipid-associated macrophages transition to an inflammatory state in human atherosclerosis, increasing the risk of cerebrovascular complications
- 2023
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Ingår i: Nature Cardiovascular Research. - 2731-0590. ; 2:7, s. 656-672
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Tidskriftsartikel (refereegranskat)abstract
- The immune system is integral to cardiovascular health and disease. Targeting inflammation ameliorates adverse cardiovascular outcomes. Atherosclerosis, a major underlying cause of cardiovascular disease, is conceptualized as lipid-driven inflammation in which macrophages play a nonredundant role. However, evidence emerging so far from single-cell atlases suggests a dichotomy between lipid-associated and inflammatory macrophage states. Here, we present an inclusive reference atlas of human intraplaque immune cell communities. Combining single-cell RNA sequencing (scRNA-seq) of human surgical carotid endarterectomies in a discovery cohort with bulk RNA-seq and immunohistochemistry in a validation cohort (the Carotid Plaque Imaging Project), we reveal the existence of PLIN2hi/TREM1hi macrophages as a Toll-like receptor (TLR)-dependent inflammatory lipid-associated macrophage state linked to cerebrovascular events. Our study shifts the current paradigm of lipid-driven inflammation by providing biological evidence for a pathogenic macrophage transition to an inflammatory lipid-associated phenotype and for its targeting as a new treatment strategy for cardiovascular disease.
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| 2. |
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| 3. |
- Fernandez-Chacon, Macarena, et al.
(författare)
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Incongruence between transcriptional and vascular pathophysiological cell states
- 2023
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Ingår i: NATURE CARDIOVASCULAR RESEARCH. - : SPRINGERNATURE. - 2731-0590. ; 2:6, s. 530-549
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Tidskriftsartikel (refereegranskat)abstract
- The Notch pathway is a major regulator of endothelial transcriptional specification. Targeting the Notch receptors or Delta-like ligand 4 (Dll4) dysregulates angiogenesis. Here, by analyzing single and compound genetic mutants for all Notch signaling members, we find significant differences in the way ligands and receptors regulate liver vascular homeostasis. Loss of Notch receptors caused endothelial hypermitogenic cell-cycle arrest and senescence. Conversely, Dll4 loss triggered a strong Myc-driven transcriptional switch inducing endothelial proliferation and the tip-cell state. Myc loss suppressed the induction of angiogenesis in the absence of Dll4, without preventing the vascular enlargement and organ pathology. Similarly, inhibition of other pro-angiogenic pathways, including MAPK/ERK and mTOR, had no effect on the vascular expansion induced by Dll4 loss; however, anti-VEGFA treatment prevented it without fully suppressing the transcriptional and metabolic programs. This study shows incongruence between single-cell transcriptional states, vascular phenotypes and related pathophysiology. Our findings also suggest that the vascular structure abnormalization, rather than neoplasms, causes the reported anti-Dll4 antibody toxicity. Fernandez-Chacon et al. use imaging and scRNA-seq after targeting multiple Notch genes and angiogenic signaling pathways to find that the function of these pathways in vascular pathophysiology cannot be predicted by assessing transcriptional states.
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| 4. |
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| 5. |
- Vestweber, Dietmar, et al.
(författare)
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Report from the 2023 workshop on endothelial permeability, edema and inflammation
- 2023
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Ingår i: Nature Cardiovascular Research. - : Springer Nature. - 2731-0590. ; 2:12, s. 1120-1124
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- A key consequence of increased and sustained vascular permeability in several inflammatory and cardiovascular disorders is the development of interstitial protein-rich proinflammatory edema. This response remains poorly understood mechanistically and its potential adverse effect on local and systemic diseases is often underestimated. To discuss current findings and identify crucial unresolved questions, a workshop was held in Berlin from 12-15 April 2023. Key topics that were discussed included regulation of endothelial cell junctions, neutrophil-dependent vascular leakage, resolution of edema, exemplar diseases, and anti-edema therapies. This report is a summary of the meeting.
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| 6. |
- Zekavat, Seyedeh M., et al.
(författare)
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TP53-mediated clonal hematopoiesis confers increased risk for incident atherosclerotic disease
- 2023
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Ingår i: Nature Cardiovascular Research. - : Springer Science and Business Media LLC. - 2731-0590. ; 2:2, s. 144-158
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Tidskriftsartikel (refereegranskat)abstract
- Somatic mutations in blood indicative of clonal hematopoiesis of indeterminate potential (CHIP) are associated with an increased risk of hematologic malignancy, coronary artery disease and all-cause mortality. Here we analyze the relation between CHIP status and incident peripheral artery disease (PAD) and atherosclerosis, using whole-exome sequencing and clinical data from the UK Biobank and the Mass General Brigham Biobank. CHIP associated with incident PAD and atherosclerotic disease across multiple beds, with increased risk among individuals with CHIP driven by mutation in DNA damage repair (DDR) genes, such as TP53 and PPM1D. To model the effects of DDR-induced CHIP on atherosclerosis, we used a competitive bone marrow transplantation strategy and generated atherosclerosis-prone Ldlr −/− chimeric mice carrying 20% p53-deficient hematopoietic cells. The chimeric mice were analyzed 13 weeks after grafting and showed increased aortic plaque size and accumulation of macrophages within the plaque, driven by increased proliferation of p53-deficient plaque macrophages. In summary, our findings highlight the role of CHIP as a broad driver of atherosclerosis across the entire arterial system beyond the coronary arteries and provide genetic and experimental support for a direct causal contribution of TP53-mutant CHIP to atherosclerosis.
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