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Arrhythmogenic cardiomyopathy is a major cause of sudden death among young people. Three studies show that gene therapy to restore the desmosomal protein PKP2 holds promise in improving the prognosis of affected individuals.
The molecular mechanisms that link propionyl-CoA metabolism and epigenetic regulation of gene expression are unclear, as are the implications for heart function. Now, new insights into the modulation of chromatin acylation and transcription by aberrant oxidation of propionyl-CoA are revealed in the dysfunctional hearts of mice with propionic acidemia.
Coronary artery calcification (CAC) is a strong predictor of coronary artery disease. A genome-wide association study of CAC in diverse populations, including 22,400 participants, identifies two previously unrecognized loci associated with CAC and provides insights into the underlying molecular mechanism of CAC.
Pregestational diabetes is linked to an increased risk of congenital disorders, including cardiac and craniofacial defects, but the underlying mechanisms are unclear. Using a hyperglycemic mouse model, Nishino et al. show that ectopic retinoic acid signaling in the anterior heart field causes aberrant tissue patterning and associated pathologies1.
TREM2 was recently found to have crucial roles in microglia and adipose tissue macrophage function. Research now shows that genetic deletion of macrophage TREM2 modulates lipid uptake, cell death susceptibility and efferocytosis and ultimately reduces experimental atherosclerosis development.
Ventricular arrhythmias are associated with aging and are a leading cause of sudden cardiac death. A new study shows that hyperactivation of p38γ/δ MAPKs is a key driver of stress-induced ventricular arrhythmias via increased phosphorylation of ryanodine receptor 2 at Ser2367 and impaired localization of potassium voltage-gated channel Kv4.3.
Effective pharmacological treatment options for abdominal aortic aneurysm (AAA) are missing. A study by Zhang et al. suggests that targeting the thrombo-inflammatory activity of platelets by blocking the intracellular accumulation of ceramides might limit AAA progression while not affecting hemostatic platelet function.
The key determinants of the passive mechanical properties of the heart have long been debated, but remain controversial. Research using a precision approach indicates that titin, microtubules, actin and the extracellular matrix each meaningfully contribute to myocardial passive stiffness in a highly context-dependent manner.
BBLN, a protein with predominantly uncharted functions, serves as an instigator of CAMK2D autophosphorylation, leading to subsequent cardiac remodeling and failure in both humans and mice. The induction of BBLN is driven by hypoxia in TOF and/or pressure overload, as evidenced in mouse models.
The incidence of acute cardiovascular events, including myocardial infarction and ischemic stroke, is increased in individuals with COVID-19. A study shows that SARS-CoV-2 can directly infect macrophages and foam cells in atherosclerotic plaques and contribute to plaque instability.
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that coordinates cellular responses to environmental stimuli. Two recent Nature papers show that endothelial AHR is responsive to dietary micronutrients, triggering a signaling cascade that supports tissue homeostasis and responses to infection.
Reduced expression of smooth muscle α-actin (αSMA), a crucial piece of the vascular smooth muscle cell cytoplasmic contractile apparatus, contributes to these cells’ dysfunction in vascular diseases. αSMA is now shown to localize in the nucleus and bind chromatin-remodeling complexes to regulate smooth muscle contractile gene expression.
Spatially resolved multiomics is an emerging approach for profiling gene expression at the cellular level while maintaining the spatial organization of tissues. Its application in healthy human hearts provides insight into ion channels and regulatory signaling in the cardiac conduction system, cardiac cellular niches and drug–cell interactions.
A method to identify and analyze clonal hematopoiesis in clinical blood samples at single-cell resolution reveals cell-intrinsic and paracrine effects of DNMT3A mutations in circulating monocytes, T cells and natural killer cells in the setting of heart failure.
Lipid remodeling, from fatty acid transport and de novo lipid synthesis, is necessary for megakaryocyte differentiation and platelet production. Dietary saturated fatty acids, impaired fatty acid transport and/or dysfunction in lipid biogenesis can contribute to low platelet counts.
Vascular inflammation is an established risk factor for atherosclerosis progression and associated outcomes. Single-cell RNA sequencing of carotid atherosclerotic plaques identifies a population of lipid-associated macrophages that may contribute to plaque inflammation and clinical events.
Genome-wide association studies have correlated a common allelic block with reduced incidence of heart failure, but the causal mechanism remains unclear. New research suggests that the C151R coding variant in the BAG3 gene is involved in the cardioprotective effect of the haplotype block by increasing cardiomyocyte protection from stress.
Structural determination of the ABCC4 transporter is a major first step in providing crucial molecular insights into the transport of platelet substrates into granules, as well as drug transport from platelets. The findings provide a framework for understanding platelet interactions and potential design of specific platelet antagonists.
Vascular patterning is dictated by transcription factors, such as the Notch pathway. Molecular profiling has uncovered snapshots of the transcriptional specification of endothelial cell tubulogenesis. Here, the authors leverage the output of Notch signaling, demonstrating that vascular remodeling is poorly predicted by transcriptional profiling.
Ranolazine is an anti-arrhythmic drug that targets voltage-gated sodium channels. Lenaeus et al. present a cryo-EM structure of the cardiac sodium channel bound to ranolazine to demonstrate that this compound acts as a structural clamp that inhibits the channels.
