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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.
We show how a build-up of propionyl-CoA in a mouse model of propionic acidaemia produces histone modifications in the heart. The transcriptional responses included genes implicated in contractile dysfunction. Notably, female mice are more severely affected, owing to a protective effect of β-alanine in males, a therapeutically important finding.
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.
BBLN, a protein with largely unknown function, was found to be upregulated in damaged hearts of children with tetralogy of Fallot, one of the most frequent congenital heart defects. Transgenic mice and in vitro studies showed that elevated BBLN levels triggered heart damage by activation of the protein CAMK2D.
Abraham and colleagues review the recent developments and future strategies to therapeutically target the endothelin pathway for a broad spectrum of cardiovascular diseases.
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.
Passive stiffness measurements in heart samples of a ‘titin-cleavage’ mouse model reveal the elastic and viscous force contributions of individual myocardial components. Titin is the principal contributor to elastic forces, whereas the microtubules and titin, followed by actin, dominate the viscous force contributions; the extracellular matrix contributes at high strain.
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.
Right ventricular failure is a major cause of morbidity and mortality in pulmonary hypertension. Transcriptomic profiling of adaptive and maladaptive right ventricular remodeling in humans adds to our basic knowledge of myocardial remodeling and identifies molecular subgroups and biomarkers.
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.
Inflammatory monocytes and macrophages in the heart express C-C chemokine receptor 2 (CCR2) on their cell surface and contribute to heart failure pathogenesis. This study established the feasibility of imaging CCR2+ cells by positron emission tomography in patients with myocardial infarction.
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.
