Volume 2 Issue 7, July 2023

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.

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.

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.

We outline protein interaction networks for 13 ion channels isolated from mouse hearts and show that several protein components are shared between ion channel networks. Multi-omic data integration couples these findings to features of the human heart electrocardiogram and we evaluate the functional effect of ten network proteins on cardiac electrophysiology.

We established a mouse model that recapitulates the clinical symptoms of Takotsubo syndrome (‘broken heart syndrome’) and revealed a causal relationship between calcineurin-dependent cardiac inflammation and disease severity. Inhibition of calcineurin as a therapeutic approach is now entering a multi-center clinical trial.

Perez-Bermejo et al. performed an in-depth study on a variant in the BAG3 gene that has been previously associated with lowered incidence of heart failure and show that, in induced pluripotent stem cell-derived cardiomyocytes engineered to express such BAG3 variant, the interactome of the corresponding BAG3 protein has changed, rendering the engineered cardiomyocytes more resistant to a well-known cardiotoxic drug.

Zhang et al. identified a protein complex that includes AmotL2 and forms a connection between VE-cadherin and actin filaments to the nuclear lamina in endothelial cells, thereby impacting cell alignment and nuclear integrity. The deletion of AmotL2 was found to provoke inflammation and abdominal aortic aneurysms, suggesting a linkage between junctional mechanotransduction and vascular disease.

The ‘Broken-heart’ or takotsubo syndrome (TTS) causes acute heart failure triggered by emotional or physical stress. Bruns et al. establish a clinically relevant mouse model of TTS and show the therapeutic potential of calcineurin inhibition in the treatment of TTS.

Dib, Koneva et al. generate an scRNA-seq atlas of immune cells from human carotid endarterectomies and report the presence of a subset of pathogenic pro-inflammatory PLIN2^hi/TREM1^hi, derived from TREM2^hi lipid-associated macrophages via TLR signaling, which correlates with an increased risk of cerebrovascular events.

Maurya et al. define interactomes of 13 major cardiac ion channels, contextualize their relevance to human electrophysiology by integrating multi-omics data that suggest that 44% of the network proteins influence human electrocardiogram, and validate the functional roles of ten interactors.

Chen et al. provide cryo-EM structures of ABC transporter ABCC4 in human platelets and, through a combination of structural and biochemical assays, demonstrate that platelet agonist TXA₂ and antagonist aspirin are substrates of ABCC4 and reveal a specific transmembrane substrate-binding pocket of ABCC4. They also found that dipyridamole is a strong competitive inhibitor against ABCC4, which supports the co-administration of dipyridamole with aspirin in clinic.