Alamandine: A Novel Component of the RAS (p 1104)
Lautner et al characterize alamandine, a novel component of the renin-angiotensin system.
The renin-angiotensin system (RAS) controls the body’s fluid levels and blood pressure. Many components of the system are known and novel participants in the network are being discovered. Lautner et al studied one such novel RAS hormone called alamandine and discovered that this heptapeptide is almost identical to another RAS component—the vasodilator angiotensin-(1–7). The 2 proteins differ by just one amino acid. Indeed, alamandine could be synthesized from angiotensin-(1–7) by decarboxylation of the amino-terminus aspartate into alanine—though, as the team showed, alamandine could also be produced by catalytic hydrolysis of angiotensin A. Like angiotensin-(1–7), alamandine induced vasodilation by promoting the release of nitric oxide from cells, but despite the close sequence and functional similarity of the two proteins, they acted through different receptors. Angiotensin-(1–7) binds a receptor called Mas, where alamandine was found to bind to MrgD—previously identified as a poor angiotensin-(1–7) receptor. Importantly, treatment of hypertensive rats with alamandine resulted in a long-lasting reduction in blood pressure. These findings not only lend insight into the complexities of the renin-angiotensin system, but may also drive the development of future anti-hypertensive therapies.
Super-Resolution Scanning Patch-Clamp of Myocytes (p 1112)
Bhargava et al devise a new trick to analyze the location and function of ion channels in living cells.
Patch-clamp recording of a cell measures the activity of ion channels, but reveals nothing as to the channels’ whereabouts. Scanning ion conductance microscopy (SICM), on the other hand, provides a detailed cell surface topography, but no information about channel activity. Given that both methods work by detecting the flow of ions into a pipette—providing a direct readout of channel activity in the case of patch-clamp, and acting as an indicator of the distance from the cell surface in SICM—researchers had hoped to combine the two and thus measure channel activity at defined locations. But there was a problem: SICM requires a pipette tip no more than 100nm in diameter, while patch-clamp pipettes should be approximately 300nm. Bhargava’s new ingenious approach is to first perform SICM with a fine-tipped pipette, then move the pipette away from the sample and tap it repeatedly against the bottom of the dish until it snaps to a diameter appropriate for patch clamp analyses—the tapping and snapping being tightly controlled by a piezo device. The snapped, or clipped, pipette is then returned to the previously scanned site for patch clamp recordings. Et voila, by one simple maneuver, researchers can go from spatial to functional analysis of their channel of interest.
Chloroquine and Pulmonary Hypertension (p 1159)
An anti-malarial drug could be effective against pulmonary arterial hypertension, report Long et al.
Pulmonary arterial hypertension (PAH) leads to an increase in pulmonary arterial smooth muscle cells (PASMCs) proliferation, while decreasing apoptosis. This causes the walls of the arteries to thicken and the blood pressure to increase. The increase in PASMC proliferation has been linked to a loss-of-function of an inhibitor of proliferation called BMPR-II. Indeed, approximately 70% of heritable cases and 10–40% of sporadic cases of the PAH are caused by mutation in this gene. Even in cases of PAH without BMPR-II mutation, expression of the protein may be reduced. BMPR-II is expressed on the surface of cells and gets degraded via the lysosomal system. Therefore, Long et al therefore considered whether preventing this turnover might help maintain BMPR-II activity and slow down the progression of PAH. They treated PASMCs in culture with the anti-malarial drug chloroquine, which is a known inhibitor of lysosomal activity and has the added benefit of inducing apoptosis. Sure enough, they found that there was a decrease in PASMC proliferation, and apoptosis increased. They also found that in a rat model of PAH, injection of chloroquine prevented pulmonary arterial wall thickening and curbed PAH progression. These promising results suggest that chloroquine could be tested clinically for the treatment of PAH patients.
- © 2013 American Heart Association, Inc.