Research Briefing

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  • We report an intronic variant of the endothelial angiopoietin receptor TIE2 that is associated with increased gene expression and decreased risk of coronary artery disease. Genetic deletion of Tie2 in hypercholesterolemic mice shows that the Tie2 receptor protects from atherosclerosis by controlling inflammation in the arterial wall.

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  • Variants in the alpha kinase 3 (ALPK3) gene cause cardiomyopathy, but we have little understanding of the mechanisms at play. We demonstrate that ALPK3 forms a critical signaling node that links contractile proteins to protein quality control machinery. These findings may open new therapeutic approaches to treat cardiomyopathies.

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  • We report a new non-invasive approach to track neutrophils in both mice and humans by directing multimodal fluorine-loaded nanotracers equipped with specific binding peptides to neutrophil surface markers to enable background-free readout by in vivo 19F MRI.

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  • Using cap analysis of gene expression, we have constructed a map of the genome regulatory network (promoters and enhancers) in healthy and failing human hearts. Analysis of this map demonstrates differential transcriptional regulation in cardiac chambers, disease states, and ischemic and non-ischemic cardiomyopathies. This information could lead to tailored therapies.

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  • Supplementation with the gut microbial-derived metabolites acetate and butyrate has been shown to lower blood pressure in experimental models of hypertension. However, the translational potential of these metabolites has been unexplored. We provide clinical evidence that acetate and butyrate lower blood pressure in untreated patients with hypertension.

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  • Endothelial cell–cell contacts in blood vessels constitute a barrier to the flux of molecules and cells from blood to tissues. We identified the tyrosine-protein kinase Yes as the principal regulator of collective endothelial cell migration and vascular barrier dynamics, a finding that opens avenues for future therapeutic development.

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  • Clustering the atherosclerotic plaques of patients based on gene expression unearths novel and clinically relevant heterogeneity beyond the established dogma of ‘stable’ and ‘unstable’ plaques.

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  • The mechanisms of adrenergic stimulation of cardiac voltage-gated calcium (CaV) channels have remained elusive. Using proximity proteomics and genetically altered mice, we show that phosphorylation of the CaV channel inhibitor Rad is essential for regulation, by the sympathetic nervous system, of calcium influx, and for augmentation of cardiac contractility.

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  • Loss of VEGF-C or VEGFR3 function or gain of VE-cadherin function causes identical defects in sinusoidal and lymphatic growth, resulting in anemia and lymphedema. Mechanistically, VEGF-C drives VE-cadherin phosphorylation and endocytosis whereas VE-cadherin prevents VEGFR3 internalization and downstream growth factor signaling. In the absence of VEGFR3, reducing VE-cadherin levels rescues vascular growth by potentiating VEGF-C–VEGFR2 signaling.

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  • GPR55 is a G protein–coupled receptor that is activated by endogenous lipid mediators. Our findings in experimental mouse models of atherosclerosis and human plaques indicate that GRP55 signaling is important for limiting B cell activation and humoral responses during hypercholesterolemia, which suggests that GPR55 signaling has an atheroprotective role.

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  • Myocardial ischemia–reperfusion injury (MIRI) substantially contributes to the morbidity associated with ischemic heart disease. Timed administration of digoxin decreased the susceptibility of mouse cardiomyocytes to MIRI; digoxin acted by promoting proteasomal degradation of the nuclear receptor REV-ERBα, a key component of the molecular circadian clock.

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  • Little is known about the maintenance of endothelial cell fate in adults. We show that deletion of Erg and Fli1 in endothelial cells of adult mice causes loss of endothelial cell fate and vascular collapse. Overexpression of ERG and FLI1 in non-vascular cells activates an endothelial cell program, confirming their regulation of endothelial cell identity.

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  • We explored age-dependent patterns in sex differences for a wide range of cardiometabolic disease risk factors and observed widespread and divergent patterns for different risk-factor groups. These findings highlight the importance of taking both age and sex into account when assessing a person’s risk of developing cardiometabolic disease.

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  • Heart failure is marked by metabolic insufficiency, but detailed understanding of the underlying metabolic rewiring has been limited. By applying state-of-the-art mass spectrometry to a large pool of human hearts in end-stage heart failure, we unveil numerous metabolic aberrations in human heart failure.

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  • Sepsis-derived S100A8/A9 induces GSDMD-dependent platelet pyroptosis via the TLR4–ROS–NLRP3–caspase 1 pathway, leading to the release of oxidized mitochondrial DNA that contributes to the formation of neutrophil extracellular traps (NETs). NETs in turn release S100A8/A9 and accelerate platelet pyroptosis, forming a positive feedback loop and thereby amplifying the production of proinflammatory cytokines.

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  • In lung tissues of pulmonary hypertension rodent models, B cell activation and immunoglobulin E (IgE) production lead to mast cell activation and release of the cytokines IL-6 and IL-13, which result in remodeling of vascular smooth muscle cells. Blockade of IgE with omalizumab, a clinically approved monoclonal antibody against IgE, alleviated the progression of experimental pulmonary hypertension.

    Research Briefing