miR-145 in Pulmonary Hypertension (p 290)
Suppressing microRNA-145 protects mice against pulmonary hypertension, report Caruso et al.
Pulmonary hypertension is a potentially fatal condition caused by a progressive increase in vascular resistance in the pulmonary arteries, which eventually leads to right-ventricle hypertrophy and heart failure. While the condition is characterized by the accumulation of smooth muscle cells in the blood vessel walls, little is known about the cause. The microRNA miR-145 has been shown to be abundant in vascular smooth muscle cells, where it regulates proliferation and differentiation. Moreover, the arteries of genetically engineered mice lacking miR-145 have thinner smooth muscle layers. Caruso et al discovered that patients with pulmonary hypertension had increased levels of miR-145 in their pulmonary artery smooth muscle cells. Mice that were induced to develop pulmonary hypertension showed a similar miR-145 increase, specifically in the lungs and right heart. Mice lacking miR-145, on the other hand, were protected from induced hypertension. Moreover, the same protection was also achieved in wild-type mice injected with an miR-145 blocker. Given the similarities between the mice and patients, the team suggests that reducing miR-145 expression may be an effective therapeutic approach.
Shh-Modified CD34 Cells for MI (p 312)
Boosting SHH in stem cells improves their ability to fix heart damage, report Mackie et al, but the findings also suggest a better treatment strategy.
CD34+ hematopoietic stem cells from the bone marrow can promote blood vessel growth in ischemic heart tissue. Consequently, using a patient's own CD34+ cells to treat heart disease has been considered as a possible therapy. However, the viability and angiogenic potential of CD34+ cells diminishes with age—just as the risk of heart disease increases. Thus, Mackie et al wondered whether the activity of CD34+ cells might be supplemented by cotreating with Shh, a well-known angiogenic factor. Interestingly, while this cotreatment was no better at repairing ischemic mouse hearts than CD34+ cells alone, when the cells were genetically modified to express more Shh, treatment improved. The modified cells reduced infarct size, increased capillary density, and preserved cardiac function more successfully than did nonmodified cells. To be effective, it turned out that Shh had to be delivered to the target tissue in exosomes—vesicles secreted from cells. The authors suggest that perhaps Shh exosomes themselves could be an even more effective therapy than the modified stem cells. Because exosomes could be harvested from cells in cultures, they would also be a more accessible form of treatment.
Nav1.8 Activity in Intracardiac Neurons (p 333)
In the heart, neurons not muscle cells house Nav1.8 sodium channels, report Verkerk et al.
The most prominent sodium channel in the heart is the voltage-gated Nav1.5 channel encoded by the SCN5A gene. However, recent genome-wide association studies have linked the gene SCN10A, which encodes the channel Nav1.8, to cardiac electrophysiology. Whether these Nav1.8 sodium channels, which are primarily found in neurons involved in pain perception, are actually present in the heart at all had been up for debate. Now, Verkerk et al have confirmed that these channels are indeed present in the heart. However, immunohistochemical analysis revealed that the channels are present on intracardiac neurons only and not on cardiomyocytes. Moreover, they found that blocking the Nav1.8 channels specifically inhibited the firing of these neurons but had no effect on atrial or ventricular cardiomyocytes. It is not yet clear how these effects of Nav1.8 in intracardiac neurons could translate to changes in cardiac conduction, but, given the fact that bradycardia occurs in mice with SCN10A gene mutations, it is clear that intraneurons and their Nav1.8 channels deserve a closer look in future arrhythmia research.
- © 2012 American Heart Association, Inc.