Nox1 Phosphorylation Mediates NoxA1 Association (p 911)
Streeter et al suggest a way to inhibit the vascular disease-causing enzyme NADPH oxidase.
Nox1 is the catalytic subunit of the enzyme NADPH oxidase, which transfers electrons from NADPH to oxygen to create damaging reactive oxygen species (ROS). The enzyme is present in a number of cell types such as vascular smooth muscle cells (VSMCs) and an increase in its activity has been linked to the development of atherosclerosis and other vascular diseases. Streeter and colleagues now show that activation of Nox1, which requires interaction with subunit NoxA1, depends on Nox1 phosphorylation. The team discovered that in the arteries of animals with vascular disease or injury—monkeys fed an atherogenic diet and rodents that sustained vessel injuries—Nox1 phosphorylation was significantly increased. They localized this phosphorylation event to tyrosine residue 429 of the protein, and showed by mutational analyses that phosphorylation of this residue was required for both association with NoxA1 and for enzyme activity. Cells containing a non-phosphorylatable version of Nox1 produced fewer ROS than those containing the wild-type protein. Together the results indicate that preventing tyrosine 429 phosphorylation of Nox1 might be a novel mechanism for diminishing vascular oxidative stress.
Ankyrin-G Signaling Platform (p 929)
Makara et al report the role of ankyrin-G in cardiomyocyte excitability.
The voltage gated sodium channel Nav1.5 is critical for excitation and conduction in cardiomyocytes. Indeed mutations to the gene encoding Nav1.5 (SCN5A) are associated with atrial fibrillation, ventricular arrhythmias and other conduction abnormalities. But surprisingly little is known about the regulation of this channel. Ankyrin proteins target ion channels to membranes in a variety of excitable cells and ankyrin-G has been shown to associate with Nav1.5 in cultured cells. To examine whether this association occurs in vivo and to assess its significance, Makara and colleagues engineered mice with a conditional heart-specific knock out of ankyrin-G. Heart cells from these mice showed a loss of Nav1.5 localization to intercalated disks—specialized junctions between heart cells where ankyrin-G and Nav1.5 both normally reside. The cells also exhibited abnormal Nav1.5-dependent sodium currents. The kinase CAMKIIδ, which phosphorylates Nav1.5, was also absent from intercalated discs and, as a result, Nav1.5 phosphorylation was reduced. The team also found that the engineered mice had cardiac conduction abnormalities and were more prone to induced arrhythmias than control mice. The study provides greater insight into the cell biology of Nav1.5, which in turn should help with the design of treatments for Nav1.5-associated arrhythmias.
CD133+ Progenitor Cells to Promote Angiogenesis (p 950)
Jimenez-Quevedo et al present the final two-year follow-up results of the PROGENITOR trial for ischemic heart disease.
Endothelial progenitor cells from the bone marrow have been used in clinical trials for ischemic heart disease with some success. But while most of these studies have used progenitors expressing the CD34+ marker, evidence suggests progenitors that also express CD133+ may be even better at promoting new vessel growth in ischemic myocardium. Jimenez-Quevedo and colleagues thus performed the PROGENITOR trial to examine the safety and efficacy of these cells in particular. In this trail, CD133+ cells were isolated from the blood of 19 patients with ischemic heart disease and transplanted into the heart tissue by transendocardial injection. Although the team saw no improvements in the objective measures of ischemic heart disease—for example, no reversal of ischemia and no improvement in heart function—a global measure of blood perfusion in the heart (the SPECT summed score) was improved in the treated patients. Improvements were also seen in these patients’ quality of life—they suffered fewer angina attacks and were slower to develop angina when subjected to treadmill tests. Overall the results of this small-scale study are sufficiently encouraging to warrant further trials, the authors say.
- © 2014 American Heart Association, Inc.