Locus Confined Control of Cardiac Tbx3 Expression (p 432)
van Weerd et al examine the 3D chromatin architecture of the Tbx3/5 locus.
The abundance, location, and timing of the expression of transcription factors such as Tbx3 and Tbx5 are critical for the precise development of the cardiac conduction system. Recently, common variations in genomic sequence surrounding the Tbx3/5 locus have been linked to conduction system anomalies that pose a risk for heart failure and sudden death in humans. To investigate whether this region contains important Tbx3/5 regulatory elements, Weerd et al used a chromatin conformation capturing technique called 4C-seq, which identifies genomic regions that interact with one another in the 3D nuclear environment. Using this technique, they found that both the Tbx3 and Tbx5 promoters interact with DNA sequences upstream and downstream of the genes themselves. But crucially, there was almost no overlap between the interaction zones for the two genes. In addition to this strict division of interactions, the team found two enhancers upstream of Tbx3 that were essential and sufficient for correct Tbx3 expression patterns in the developing mouse heart. Surprisingly, however, these enhancers interacted with the Tbx3 promoter regardless of the cell type. These findings not only further our understanding of the chromatin architecture and transcriptional control of Tbx3 and Tbx5 but also provide insight into how the conduction system develops and how the nearby genetic variations can lead to conduction anomalies.
Arginase 2 Translocation by OxLDL (p 450)
Blocking arginase 2 activity reduces severity of atherosclerosis, report Pandey et al.
The amino acid L-arginine is a substrate of nitric oxide synthase (NOS) used in the production of the important vasodilator nitric oxide. But L-arginine is also a substrate for arginase, suggesting that arginase might regulate NOS activity by means of substrate competition. Oxidized low-density lipoprotein (OxLDL, or bad cholesterol) is known to increase arginase 2 activity in human vascular endothelial cells, which could therefore decrease NO production and lead to vascular injury and dysfunction. Nevertheless, how OxLDL increases arginase 2 is unclear. Pandey et al have now shown that OxLDL prompts arginase 2 to relocate from its depot in the mitochondria to the cytoplasm where activity of the enzyme is higher. They also showed that this translocation requires cleavage of arginase 2 by the mitochondrial processing peptide, MPP. The team confirmed that OxLDL led to upregulation of MPP and showed that in atherosclerosis-prone mice, deletion of the arginase 2 gene led to smaller plaques as well as increased NO production and decreased reactive oxygen species in the aortic intima. Collectively, these results suggest that inhibiting arginase 2, by the activation of MPP or other means, could be a novel strategy for anti-atherosclerosis therapy.
SEMA3A in Brugada Syndrome (p 460)
Neuronal factor semaphorin 3A plays a novel role in cardiac conduction, report Boczek et al.
Semaphorins are developmental factors that guide the growth and migration of neurons, including those that innervate the heart. But intriguingly, semaphorin 3A (SEMA3A) has a domain that is highly similar to hanatoxin—found in the venom of tarantulas. Hanatoxin is an inhibitor of voltage-gated potassium channels, leading Boczek and colleagues to wonder whether SEMA3A could do the same. In cell culture experiments, they showed that SEMA3A did indeed reduce the current produced by potassium channel Kv4.3. And in human and mouse heart tissue preparations, they found that SEMA3A and Kv4.3 interact with each other. They also found that of 198 patients with Brugada syndrome—characterized by abnormal electrical activity in the heart and increased risk of arrhythmia—10 had mutations in SEMA3A, and two of these mutations were absent from approximately 20,000 control individuals, suggesting these mutations might be pathological. Indeed, studies showed that cells containing these mutant versions of SEMA3A had higher Kv4.3 activity compared with cells containing wild-type SEMA3A. Since an increase in Kv4.3 activity has been described in some Brugada syndrome patients, Boczek and colleagues suggest targeting the SEMA3A/Kv4.3 interaction as a novel therapeutic strategy.
- © 2014 American Heart Association, Inc.