Inhibition of miR-155 Reduces Myocardial Damage (p 415)
Blocking the activity of a microRNA called miR-155 could improve the outcome of viral myocarditis, report Corsten et al.
Certain viruses, such as coxsackievirus, make a beeline for the heart, where they infect cells, replicate, and generally wreak havoc. The resulting viral myocarditis could cause irreversible cardiomyocyte damage and interstitial fibrosis, which can lead to heart failure and sudden cardiac death. Corsten et al have now discovered that miR-155 worsens this viral damage. The authors analyzed differentially expressed miRs in coxsackievirus-susceptible versus coxsackievirus-resistant mice. They found a large number of such miRs, of which only 16 were also found to be changed in human patients with viral myocarditis. The authors focused on one of the 16 miRs, namely miR-155, because it is known to be involved in inflammation. The authors discovered that in inflamed mouse and human hearts, miR-155 expression was significantly ramped up in infiltrating inflammatory cells, particularly in T cells and macrophages. Blocking miR-155 activity in mice with a targeted synthetic nucleic acid reduced both cardiac inflammation and injury and improved cardiac function and mouse survival. miR-155 might therefore be a potential therapeutic target to improve the prognosis of patients with viral myocarditis, say the team.
Sema3A Role in Lymphatic Vessel Development (p 426)
A neuronal guidance molecule doubles as a drainage developer, helping to shape growing lymph vessels, report Jurisic et al.
Despite the importance of the lymphatic system for tissue fluid homeostasis, immune system functioning, and more, relatively little is known about the molecular mechanisms of lymph vessel development. To gain clues as to the molecules involved, Jurisic and colleagues performed an expression profile analysis on lymphatic endothelial cells, comparing them with blood endothelial cells. Besides the expected lineage-specific gene expression differences, 2 particular proteins—semaphorin 3A and 3D—were highly expressed in the lymph cells. These proteins, which are better known for their roles in neuronal guidance, were also upregulated in human lymph endothelium. Blocking the binding of semaphorin to its receptor Nrp-1 during mouse embryonic development at the stage when lymph vessels are forming led to impaired lymph drainage after birth. In treated 5-day-old mice, tissues failed to drain properly; the mice had irregularly shaped lymph vessels, including an overabundant covering of smooth muscle cells. While there are still many unanswered questions about exactly how semaphorin regulates smooth muscle cell accumulation and vessel formation, the findings should prove useful in future research into lymph vessel disorders, such as lymphedema.
MitoROMK: A Subunit of MitoKATP (p 446)
Foster et al identify the potassium channel behind the protective effects of preconditioning.
Preconditioning is a cardioprotective effect, whereby a brief episode of ischemia actually prepares the heart to cope with future prolonged ischemic insult and avoid infarction. It was known that preconditioning could be prevented by potassium channel blockers and mimicked by potassium channel openers. A particularly potent mimic of preconditioning is the drug diazoxide, which primarily regulates potassium flux at the mitochondria. However, the physical channel responsible for the potassium flux and thus for protection had not been identified and characterized. Foster et al used an unbiased proteomics approach to find the elusive channel. From some 20 million mass spectrometry spectra of isolated mitochondrial membranes, they identified 186 likely proteins that were not previously identified in the heart. Two of these identified peptides matched a highly expressed kidney potassium channel called ROMK. Expression analysis confirmed that ROMK RNA was present in the neonatal and adult rat heart and that the protein localized to mitochondria. Furthermore, overexpression of ROMK protected heart-derived cells against induced cell death, whereas knockdown of ROMK exacerbated cell death. The identification of ROMK provides a target for future cardioprotective therapeutic interventions.
Written by Ruth Williams
- © 2012 American Heart Association, Inc.