Volume 1 Issue 11, November 2022

Studies of the genetic architecture of cardiovascular disease once focused on heritable germline factors. Newer work has shed light on the role of somatic mutations in blood cells. These mechanistic and multi-omics studies, along with phenotypic analyses, offer the prospect of new precision cardiovascular medicine paradigms.

The COVID-19 pandemic has unleashed a tidal wave of psychological distress. Here we discuss the biobehavioral mechanisms through which psychological distress amplifies the adverse effects of SARS-CoV-2 infection on cardiovascular outcomes. We also examine how the stress of caring for patients with COVID-19 increases cardiovascular risk in healthcare workers.

Myocardial ischemia–reperfusion injury is more severe during the sleep-to-wake transition period of the day. A new study shows that timed administration of digoxin, a cardiac glycoside approved by the US Food and Drug Administration, prevents experimental myocardial ischemia–reperfusion injury by controlling proteostasis of the circadian-clock regulator Rev-Erbα.

Sinusoidal vessels are specialized vascular structures required for hematopoiesis. A new study demonstrates a role for VEGF-C–VEGFR3 signaling in the development of sinusoidal vessels and a previously unappreciated reciprocal regulatory relationship between VE-cadherin and VEGFR3.

The border zone in myocardial infarction is of key importance for the remodeling process that drives heart failure and sudden cardiac death. Two studies have now performed single-nucleus and spatial mapping of mouse myocardial infarction to provide novel insights into spatiotemporal events in the border zone.

The rapid enhancement of cardiac Ca²⁺ current (I_Ca,L) is central to enhanced heart function during the sympathetic fight-or-flight response. A new study shows how the small GTPase Rad mediates tonic I_Ca,L inhibition that is relieved after PKA-dependent phosphorylation of Rad, which causes release of Rad from the Ca²⁺ channel and increased I_Ca,L.

B cells have an essential role in regulating atherogenesis. A new study shows that the orphan receptor GPR55 is a pivotal modulator of B cell maturation and immunoglobulin production. This new finding identifies a previously uncharacterized protein involved in regulation of atherosclerosis by the immune system.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.