| First Author | Chelko SP | Year | 2016 |
| Journal | JCI Insight | Volume | 1 |
| Issue | 5 | PubMed ID | 27170944 |
| Mgi Jnum | J:235770 | Mgi Id | MGI:5800642 |
| Doi | 10.1172/jci.insight.85923 | Citation | Chelko SP, et al. (2016) Central role for GSK3beta in the pathogenesis of arrhythmogenic cardiomyopathy. JCI Insight 1(5) |
| abstractText | Arrhythmogenic cardiomyopathy (ACM) is characterized by redistribution of junctional proteins, arrhythmias, and progressive myocardial injury. We previously reported that SB216763 (SB2), annotated as a GSK3beta inhibitor, reverses disease phenotypes in a zebrafish model of ACM. Here, we show that SB2 prevents myocyte injury and cardiac dysfunction in vivo in two murine models of ACM at baseline and in response to exercise. SB2-treated mice with desmosome mutations showed improvements in ventricular ectopy and myocardial fibrosis/inflammation as compared with vehicle-treated (Veh-treated) mice. GSK3beta inhibition improved left ventricle function and survival in sedentary and exercised Dsg2 mut/mut mice compared with Veh-treated Dsg2 mut/mut mice and normalized intercalated disc (ID) protein distribution in both mutant mice. GSK3beta showed diffuse cytoplasmic localization in control myocytes but ID redistribution in ACM mice. Identical GSK3beta redistribution is present in ACM patient myocardium but not in normal hearts or other cardiomyopathies. SB2 reduced total GSK3beta protein levels but not phosphorylated Ser 9-GSK3beta in ACM mice. Constitutively active GSK3beta worsens ACM in mutant mice, while GSK3beta shRNA silencing in ACM cardiomyocytes prevents abnormal ID protein distribution. These results highlight a central role for GSKbeta in the complex phenotype of ACM and provide further evidence that pharmacologic GSKbeta inhibition improves cardiomyopathies due to desmosome mutations. |
