Atg7 Induces Autophagy (p 151)
Encouraging heart cells to clean up their trash could help prevent cardiomyopathies, suggest Pattison et al.
Accumulation of cellular trash in the form of cytotoxic misfolded proteins is a characteristic of several cardiomyopathies. Under normal conditions, such protein trash is cleared from cells by, among other pathways, autophagy. During this process, membranous vesicles, called autophagosomes, form around protein and organelle debris and transfer it to the acidic lysosomes for destruction. So far, only a handful of factors involved in autophagy have been identified. Pattison and colleagues focused specifically on one called Atg7 and investigated whether they could use it to boost autophagy in a rat cell model of desmin-related cardiomyopathy. Overexpression of Atg7, they showed, reduced the levels of protein aggregates in model cells and increased the amount of autophagic structures. Importantly, it also reduced cytotoxicity. Conversely, suppressing Atg7 expression by siRNA inhibited autophagy and exacerbated the myopathic phenotype of model cells. The next step, says the team, is to see whether Atg7 overexpression in vivo can also boost autophagy and thus slow, or even prevent, cardiomyopathies.
MAFbx Mediates Cardiac Hypertrophy (p 161)
Curbing expression of MAFbx could protect hypertrophic hearts from progressing to heart failure, say Usui et al.
The role of enzyme MAFbx is to tag specific proteins—by adding ubiquitin groups—and dispatch them to the proteasome for destruction. Because of the large degree of protein turnover that occurs in cardiac hypertrophy and remodeling, the ubiquitin-proteasome pathway, and MAFbx itself, have been implicated in this pathology. In a previous study, MAFbx overexpression was found to suppress hypertrophy. Complimentary MAFbx loss-of-function studies had never been done, however. Usui et al have now completed the picture by studying hypertrophy in mice lacking MAFbx. Surprisingly, they found that the loss of MAFbx inhibited hypertrophy and reduced cardiac dysfunction and remodeling. Further studies showed that levels of the transcription factor NF-κB and its gene targets were also reduced. MAFbx normally targets an NF-κB inhibitor for destruction, explain the authors. The previous study's contrasting results suggest that overexpressing MAFbx leads to the degradation of additional targets besides the NF-κB inhibitor and that this somehow suppresses hypertrophy. Whatever the reason, Usui et al say that suppressing endogenous MAFbx or NFκB could be a therapeutic strategy for preventing heart failure.
AnkG: A Component of Intercellular Junctions (p 193)
AnkG is a molecular linchpin at heart cell boundaries, report Sato et al.
Intercalated discs are the specialized cell-to-cell contacts between cardiac myocytes that enable synchronized contraction across the tissue. The contacts contain physical connections, such as desmosomes, gap junctions, and adherens junctions, as well as other communication complexes, such as sodium channels. These individual structures were traditionally considered to be separate entities, but accumulating evidence suggests that they might be interconnected. Sato et al add to that evidence by showing the sodium channel component and cytoskeletal adaptor, AnkG, is associated both with desmosome protein, PKP2, and gap junction protein, Cx43. Loss of AnkG in cardiomyocytes altered the subcellular distribution of PKP2 and decreased the levels of Cx43, the team showed. Intercellular adhesion was also reduced, as was electrical coupling. Similarly, a loss of PKP2 decreased the abundance of AnkG and altered the distribution of sodium channels. Loss of gap junction components at intercalated discs has been implicated in arrhythmogenic right ventricular cardiomyopathy (ARVC). In light of these results, it appears that future studies of ARVC and other arrhythmias might be best approached by considering intercalated discs as singular complex units, suggest the team.
Written by Ruth Williams
- © 2011 American Heart Association, Inc.