Research articles

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.

Jin and coauthors show that Yes-mediated tyrosine phosphorylation is critical for VE-cadherin’s constitutive internalization and junctional pliability in endothelial cells, but it is not required for the induction of vascular leakage.

Komuro et al. performed an integrative analysis of single-nucleus RNA sequencing and spatial transcriptome analysis of the injured heart to map cellular and molecular changes across topographical domains relative to the site of injury, and they identify that mechano-sensing genes at the border zone act as adaptive regulators of left ventricular remodeling.

Using single-cell/single-nucleus RNA sequencing and spatial transcriptomic analysis, Calcagno and Taghdiri et al. define the ischemic border zone—the area between the poorly perfused infarct area and the remote zones of the heart—based on the cardiomyocyte transcriptomes. The transcriptional border zone emerges within an hour of the ischemic injury and can be observed in response to any injury that causes loss of neighboring cells and mechanical destabilization, including the trauma induced with a fine needle.

Papa et al. show that phosphorylation by PKA of four residues in Rad, a calcium channel inhibitor, is required to mediate the β-adrenergic-induced increase in calcium current and contractile force. Additionally, Rad-phosphosite-mutant mice showed reduced basal heart rate and contractility. Conversely, expression of mutant calcium channel unable to bind wild-type or phosphosite-mutant Rad was sufficient to enhance basal calcium influx and contractility, independently of β-adrenergic stimulation.

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.

Warthi et al. generated an alpha 8 integrin-cre driver that enables gene targeting preferentially in vascular smooth muscle cells (SMCs) and showed in a proof-of-principle study, that using the Itga8-CreER^T2 knock-in mouse for selective ablation of the Srf gene caused vascular defects but not a lethal visceral myopathy observed in an SMC-specific Myh11-CreER^T2-driven Srf loss.

Using different genetic mice models, Sung et al. show that VEGF-C/VEGFR3 signaling is required for sinusoidal vascular growth in the fetal liver and bone marrow. CDH5 (VE-cadherin) negatively regulates VEGF-C/VEGFR3 signaling and sinusoidal and lymphatic growth. Loss of CDH5 enables growth of sinusoidal and lymphatic vessels in the absence of VEGFR3 signaling through VEGF-C/VEGFR2 signaling.

The heart’s tolerance to ischemia–reperfusion injury varies according to a day–night cycle. Vinod et al. show that a timed low dose of cardiac glycosides, such as digoxin, is protective against heart ischemia–reperfusion injury by promoting the proteasomal degradation of the molecular-clock component and transrepressive nuclear receptor REV-ERBα.

Macias et al. generated a mouse model recapitulating the electrophysiological features of Andersen–Tawil syndrome type 1 (ATS1), a disease associated with life-threatening arrhythmias, via AAV-mediated in vivo expression of trafficking-deficient mutant Kir2.1^Δ314-315 channel. The authors identify functional Kir2.1 receptors in sarcoplasmic reticulum (SR) microdomains and report that the ATS1 arrhythmogenic phenotype is due to the dysfunction of Kir2.1 receptors both in the sarcolemma and in the SR domains.

Rodrigues et al. show that estrogen levels regulate bone endothelial cell (BEC) physiology. Low levels of estrogens impair fatty acid metabolism in BECs and lipolysis of adipocytes and cause accumulation of lipid peroxides (LPOs), leading to vascular aging. Inhibition of LPO generation significantly improved bone health in adult mice.

Mantri et al. used spatial transcriptomics and scRNA-seq combined with smFISH to characterize the pathogenesis of reovirus-induced myocarditis in neonatal mice. They report a key role for endothelial cells in modulating the inflammatory response to the virus and a role for cytotoxic T-cell-induced pyroptosis in the cardiac pathology.

In a combined computational and multi-center clinical study to investigate the effects of adipose fat tissue infiltration on ventricular arrhythmias, Sung et al. show that infiltrating adipose tissue, as opposed to scar, is the main cause of infarcted-related ventricular arrhythmias by slowing cardiac conduction in critical sites.

Gomez-Salinero, Itkin et al. demonstrate the cooperative role of two ETS transcriptor factors, ERG and Fli1, in the active maintenance of endothelial cell homeostatic function. Loss of these two genes in adult mice leads to multi-organ failure, hyperinflammation, systemic thrombosis and death. In vitro, expression of both ERG and FLI1 induces human adult non-vascular mesenchymal stromal cells to acquire endothelial-like properties. In humans, several cardiovascular disorders and inflammatory-related diseases are linked to mutations in both genes.

Destici, Zhu, et al. identify human-specific cis-regulatory elements (CREs) through a comparative epigenomic analysis of human and mouse cardiomyocytes at early stage of development and show that these CREs could contribute to species-specific cardiac features. Human-specific enhancers were particularly enriched in SNPs associated with human-specific traits (such as increased heart resting rate, atrial fibrillation and QRS duration), and the acquisition of human-specific enhancers could expand the functionality of the conserved transcriptional regulator ZIC3 by modifying its spatio-temporal expression.

With the use of the Lifelines cohort, Zhernakova and colleagues set out to characterize sex differences in cardiometabolic risk factors, metabolites and proteins in adults aged 20–80 years and find a strong age effect on sex differences in cardiometabolic disease risk factors and biomarkers.

Caudal, Tang, et al. use isobaric quantitative protein interaction reporter (iqPIR) technology to compare the mitochondrial protein interactome in healthy and failing murine hearts, providing molecular-level insights into complex mitochondrial remodeling in heart failure.

Arany and colleagues integrate metabolomics data, tissue RNA-sequencing data and proteomics data from explanted hearts of patients with end-stage heart failure to provide a comprehensive ‘multi-omic’ evaluation of the metabolic pathways affected by heart failure.

Anbazhakan et al. use whole-organ imaging and three-dimensional computational fluid dynamics modeling to define spatial architecture and predict blood flow through collaterals in neonate and adult mouse hearts after injury, and compare their findings to the functionality of collaterals in human adult and fetal hearts.

Ngwenyama et al. show that cardiac fibroblasts express MHCII during cardiac inflammation, and are able to process extracellular proteins into small peptides that induce CD4⁺ T cell immune responses. Conditional deletion of MHCII in cardiac fibroblasts ameliorates cardiac remodeling and dysfunction induced by cardiac pressure overload, supporting a central role for cardiac fibroblast MHCII in antigen presentation and in cardiac fibrosis and dysfunction in experimental HF.