J007 Cardiac remodeling following chronic activation of the Notch signaling pathway

Abstract

The Notch signaling pathway is a communication system between adjacent cells, mediated by transmembrane receptors (Notch1-4) and ligands (Jagged1 and 2, Delta-like1, 3, and 4). Notch is essential for the development and homeostasis of several self-renewing organ systems. Notch is also essential in the developing heart, and mutations in Notch genes cause cardiac malformations and congenital heart disease. Recently, using loss-of-function studies, we showed that the Notch1 receptor controlled the response to injury in the adult heart by limiting myocyte hypertrophy, enhancing myocyte survival, promoting precursor proliferation, controlling cardiogenic differentiation, and reducing interstitial fibrosis. In addition, our data suggested that upregulation of Jagged1 expression constituted a primary response in the stressed myocardium, suggesting that this ligand mediated Notch signaling in the postnatal heart. Therefore, to analyze the effects of a chronic Jagged1-induced Notch activation on the cardiac response to stress, we generated transgenic mice overexpressing Jagged1 in cardiomyocytes using the α-myosin heavy chain gene promoter (TGMHCJ1 mice). These mice expressed 100-500 fold Jagged1 mRNA relative to wild-type (WT) controls. The overexpression of Jagged1 on the surface of cardiomyocytes was confirmed by Western blotting and immunofluorescence staining. Consequently, the percentage of cardiac cells with an activated Notch pathway was higher in TGMHCJ1 mice than in WT animals. The expression of the Notch target genes Hes1 and Hey2 was also activated. Echocardiographic analysis under basal conditions revealed an enlargement of the right ventricle (RV) with a diminished left ventricle (LV) mass and chamber size in adults. TGMHCJ1 mice displayed increased juvenile mortality. The severity of the phenotype was dependent on the level of Jagged1 expression. Immunofluorescence analysis revealed myocyte hypertrophy and disarray in the RV of TGMHCJ1 mice whereas, myocytes in the LV were not affected. Moreover, when subjected to transaortic constriction (TAC), TGMHCJ1 mice demonstrated an impaired LV hypertrophic response to pressure overload and reduced cardiac fibrosis. These results indicate that chronic activation of Notch affects differently left and right ventricle integrity under physiological and pathological conditions.