| First Author | Ackermann MA | Year | 2017 |
| Journal | J Mol Cell Cardiol | Volume | 112 |
| Pages | 49-57 | PubMed ID | 28870505 |
| Mgi Jnum | J:256839 | Mgi Id | MGI:6101963 |
| Doi | 10.1016/j.yjmcc.2017.08.015 | Citation | Ackermann MA, et al. (2017) TGF-beta1 affects cell-cell adhesion in the heart in an NCAM1-dependent mechanism. J Mol Cell Cardiol 112:49-57 |
| abstractText | The contractile property of the myocardium is maintained by cell-cell junctions enabling cardiomyocytes to work as a syncytium. Alterations in cell-cell junctions are observed in heart failure, a disease characterized by the activation of Transforming Growth Factor beta 1 (TGFbeta1). While TGFbeta1 has been implicated in diverse biologic responses, its molecular function in controlling cell-cell adhesion in the heart has never been investigated. Cardiac-specific transgenic mice expressing active TGFbeta1 were generated to model the observed increase in activity in the failing heart. Activation of TGFbeta1 in the heart was sufficient to drive ventricular dysfunction. To begin to understand the function of this important molecule we undertook an extensive structural analysis of the myocardium by electron microscopy and immunostaining. This approach revealed that TGFbeta1 alters intercalated disc structures and cell-cell adhesion in ventricular myocytes. Mechanistically, we found that TGFbeta1 induces the expression of neural adhesion molecule 1 (NCAM1) in cardiomyocytes in a p38-dependent pathway, and that selective targeting of NCAM1 was sufficient to rescue the cell adhesion defect observed when cardiomyocytes were treated with TGFbeta1. Importantly, NCAM1 was upregulated in human heart samples from ischemic and non-ischemic cardiomyopathy patients and NCAM1 protein levels correlated with the degree of TGFbeta1 activity in the human cardiac ventricle. Overall, we found that TGFbeta1 is deleterious to the heart by regulating the adhesion properties of cardiomyocytes in an NCAM1-dependent mechanism. Our results suggest that inhibiting NCAM1 would be cardioprotective, counteract the pathological action of TGFbeta1 and reduce heart failure severity. |
