Imaging Ca2+ Nanosparks in Heart (p 412)
Shang et al develop a new calcium-sensitive probe to measure calcium nanosparks in dyads of the sarcoplasmic reticulum and the surface membrane.
During excitation-contraction (EC) coupling, the influx of calcium through the voltage-gated calcium channel triggers the release of calcium from the intracellular stores via the ryanodine receptor. This process of calcium-induced calcium release also controls calcium influx in the myocyte via retrograde coupling. Such transient changes in myocyte calcium levels have been extensively studied using calcium-sensitive bioluminescent probes and fluorescent indicators. While the use of these diffusible probes has provided detailed information about the nature of the calcium transient, they do not accurately reveal the behavior of the ryanodine receptor in the microdomain of dyads formed by the close apposition of the surface membrane and the sarcoplasmic reticulum (SR). Hence, to more accurately measure calcium changes in these nanoscopic dyads, Cheng and coworkers developed a new calcium biosensor in which a calcium-sensitive protein (GCaMP6f) is fused to other proteins (triadin 1 or junction) that localize to the junctional SR. By genetically targeting the probe to dyadic clefts, the authors were able to obtain high resolution, ultra-sensitive images of junctional calcium transients, or “calcium nanosparks,” within a volume that was 50 times smaller than those accessible with conventional diffusible indicators. Because conditions such as heart failure and cardiac arrhythmias are often associated with dyssynchronous calcium release, the use of these probes could provide more accurate measurements of disease-induced changes in local calcium release events.
The Hippo Pathway in Arrhythmogenic Cardiomyopathy (p 454)
Adipogenic differentiation of cardiac myocytes during arrhythmogenic cardiomyopathy is linked to the activation of the Hippo pathway, say Chen et al.
Arrhythmogenic Cardiomyopathy (AC) is a hereditary disease in which cardiac myocytes, mainly those in the right ventricle, are replaced by fibro-adipocytes. The disease often leads to cardiac arrhythmias, heart failure and even sudden cardiac death. Mutations in genes that encode desomosome proteins have been identified as the underlying cause; however, the molecular mechanism by which these mutations lead to disease phenotype remains unknown. Marian and colleagues now report that the so-called Hippo pathway is activated in human hearts with AC, as well as in mouse models of the disease. They found extensive changes in the expression and localization of several proteins in the intercalated discs (IDs) in AC hearts. Not only the activation of the Hippo pathway linked, in part, to a reduced junctional localization of PKCalpha, but it was also associated with the suppression of the canonical Wnt signaling, which regulates cell fate and differentiation. The authors propose that these changes alter the myogenic program and increase the expression of adipocyte genes in cardiac myocytes. As a whole, these findings provide new insights into the role of ID proteins in regulating cell fate and differentiation, and how their molecular remodeling changes myocyte phenotype, as well as the cell-cell interactions that lead to the pathological manifestations of AC.
3-Hydroxykynurenine and Endothelial Dysfunction (p 480)
Wang et al report that activation of tryptophan metabolism contributes to endothelial dysfunction by increase the generation of reactive oxygen species by NADPH oxidase.
Endothelial dysfunction is a key contributing factor in the development of cardiovascular disease. It is characterized by increased apoptosis of endothelial cells and decreased endothelium-dependent relaxation of blood vessels. While many factors have been shown to contribute to impaired endothelial function, several studies have linked an increase in the local generation of reactive oxygen species (ROS) to endothelial dysfunction. Now, Zou and colleagues report new evidence showing that endothelial dysfunction may actually be linked to the activation of the kynurenine (Kyn) pathway, the major route for tryptophan metabolism in mammals. They found that treatment with angiotensin II, a major inducer of endothelial dysfunction, increased Kyn production via an interferon-gamma-dependent mechanism. This increase in Kyn production was associated with increased activation of the NADPH oxidase, which induced endothelial cell apoptosis by generating high levels of superoxide. Because endothelial injury was diminished in mice lacking components of NADPH oxidase or the kynurenine pathway, the authors suggest that the activation of tryptophan metabolism leads to an upregulation of NADPH oxidase, which in turn causes endothelial injury. Based on these findings they propose that inhibiting Kyn formation may be a potentially gainful strategy for preventing endothelial dysfunction in cardiovascular disease.
- © 2014 American Heart Association, Inc.