Abstract 11619: Control of Cardiac Hypertrophy and Fibrosis by the Notch Pathway
The Notch pathway is a cellular communication system, which is mediated by transmembrane receptors and ligands expressed on adjacent cells. We demonstrated previously the importance of Notch1 (receptor) and Jagged1 (ligand) interaction in maintaining cardiac integrity in the adult heart. In the present study, we investigated the effects of a chronic activation of the Notch1 pathway on the adaptation of the heart to stress. We generated transgenic mice overexpressing Jagged1 in cardiomyocytes (TGJ1 mice). As a consequence, Notch1 was activated in both cardiac myocytes and non-myocyte cells. TGJ1 mice demonstrated a sustained proliferation of cardiomyocytes during the first weeks after birth, which lead to an increased myocyte content in the left and right ventricle walls. In the transaortic constriction (TAC) model, TGJ1 mice showed a markedly reduced cardiac hypertrophic response to pressure overload. Accordingly, the Akt-mTOR pathway was not activated in transgenic hearts under stress. Importantly, cardiac fibrosis was greatly diminished in TGJ1 mice. At the molecular levels, the expression of profibrotic factors such as TGF-beta2 and CTGF was also significantly downregulated. We next determined whether stress induced proliferation in the myocyte population in transgenic hearts using a BrdU incorporation assay. We detected higher numbers of proliferating Nkx2.5-positive cells in the heart of transgenics after TAC. On the contrary, the amounts of smooth-muscle actin-positive myofibroblasts were dramatically reduced. As a result, the numbers of cardiac myocyte and non-myocyte cells expressing Nkx2.5 were increased in the heart of TGJ1 mice. Taken together, these data demonstrate that activation of the Notch1 pathway in the stressed heart produces beneficial effects via its regulatory action on cardiac hypertrophy and fibrosis, possibly secondary to a stimulation of new myocyte generation.
- © 2011 by American Heart Association, Inc.