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Control of the adaptive response of the heart to stress via the Notch1 receptor pathway.

ABSTRACT: In the damaged heart, cardiac adaptation relies primarily on cardiomyocyte hypertrophy. The recent discovery of cardiac stem cells in the postnatal heart, however, suggests that these cells could participate in the response to stress via their capacity to regenerate cardiac tissues. Using models of cardiac hypertrophy and failure, we demonstrate that components of the Notch pathway are up-regulated in the hypertrophic heart. The Notch pathway is an evolutionarily conserved cell-to-cell communication system, which is crucial in many developmental processes. Notch also plays key roles in the regenerative capacity of self-renewing organs. In the heart, Notch1 signaling takes place in cardiomyocytes and in mesenchymal cardiac precursors and is activated secondary to stimulated Jagged1 expression on the surface of cardiomyocytes. Using mice lacking Notch1 expression specifically in the heart, we show that the Notch1 pathway controls pathophysiological cardiac remodeling. In the absence of Notch1, cardiac hypertrophy is exacerbated, fibrosis develops, function is altered, and the mortality rate increases. Therefore, in cardiomyocytes, Notch controls maturation, limits the extent of the hypertrophic response, and may thereby contribute to cell survival. In cardiac precursors, Notch prevents cardiogenic differentiation, favors proliferation, and may facilitate the expansion of a transient amplifying cell compartment.

SUBMITTER: Croquelois A

PROVIDER: S-EPMC2605223 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Control of the adaptive response of the heart to stress via the Notch1 receptor pathway.

Croquelois Adrien A Domenighetti Andrea A AA Nemir Mohamed M Lepore Mario M Rosenblatt-Velin Nathalie N Radtke Freddy F Pedrazzini Thierry T

The Journal of experimental medicine 20081208 13

In the damaged heart, cardiac adaptation relies primarily on cardiomyocyte hypertrophy. The recent discovery of cardiac stem cells in the postnatal heart, however, suggests that these cells could participate in the response to stress via their capacity to regenerate cardiac tissues. Using models of cardiac hypertrophy and failure, we demonstrate that components of the Notch pathway are up-regulated in the hypertrophic heart. The Notch pathway is an evolutionarily conserved cell-to-cell communica ...[more]

PMID: 19064701

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Project description:PURPOSE:Oestrogen receptor ? is believed to exert a cardioprotective effect against ischaemic injury. Nonetheless, the mechanism underlying its protective action remains to be fully elucidated. Recently, increased attention has been focused on Notch1 signalling for ameliorating cardiac ischaemic injury. Here, we hypothesised that oestrogen receptor ? activation attenuates myocardial infarction (MI)-induced cardiac damage by modulating the Notch1 signalling pathway. METHODS:Male C57BL/6 mice were used to establish an MI model through the ligation of the anterior descending branch of the left coronary artery. Two chemical drugs, 2,3-Bis(4-hydroxyphenyl)-propionitrile (DPN) and N-[N-(3,5-difluorophenacetyl)-l-alanyl]-s-phenylglycine t-butyl ester (DAPT), a specific inhibitor of Notch1 signalling) were administered via intraperitoneal injection to change oestrogen receptor ? and Notch1 activities. Immunohistochemistry, western blot analysis, enzyme-linked immunosorbent assay (Elisa) assessment and echocardiography were used in this study to analyse cardiac oxidative stress, apoptosis, infraction volume, fibrosis and cardiac function. RESULTS:DPN-mediated oestrogen receptor ? activation effectively protected cardiomyocytes from MI-induced oxidative damage and apoptosis. Furthermore, oestrogen receptor ? activation reduced the infarct size and lowered the levels of myocardial enzymes in the serum, thereby leading to greater overall cardiac function improvement. Ischaemic injury-induced myocardial fibrosis was attenuated by oestrogen receptor ? activation. Nevertheless, all of these cardioprotective effects of oestrogen receptor ? activation were almost abrogated by DAPT administration, i.e. DAPT attenuated the anti-oxidative and anti-apoptotic effects and the decrease in infarct and fibrotic areas and reversed cardiac functional recovery. The levels of phospho-phosphatidylinositol-3-kinase (PI3K) and phospho-protein kinase B (Akt) were increased after DPN administration, and this change was reversed after DAPT was administered. CONCLUSIONS:All of these new findings indicate that oestrogen receptor ? activation is effective in ameliorating MI-induced cardiac dysfunction by enhancing Notch1 signalling and that PI3K/Akt signalling is the downstream mediator.

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Control of the adaptive response of the heart to stress via the Notch1 receptor pathway.

Publications

Control of the adaptive response of the heart to stress via the Notch1 receptor pathway.

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