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Importance of the Notch pathway in cardiac tissue homeostasis

English title Importance of the Notch pathway in cardiac tissue homeostasis
Applicant Pedrazzini Thierry
Number 127590
Funding scheme Project funding
Research institution Service de Cardiologie Département de Médecine CHUV
Institution of higher education University of Lausanne - LA
Main discipline Cardiovascular Research
Start/End 01.10.2009 - 30.09.2012
Approved amount 468'000.00
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Keywords (12)

Heart; Remodeling; Stem cells; Physiology; Transgenic; Knockout; Myocardial infarction; Heart failure; Regeneration; Cell therapy; Transgenic mice; Notch

Lay Summary (English)

Lead
Lay summary
In high-income countries, coronary artery disease is one of the most frequent cardiovascular disorders, and leads to acute myocardial infarction. Myocardial infarction frequently progresses into maladaptive cardiac remodeling and heart failure. Ultimately, transplantation remains the only therapeutic option. However, the lack of organ donors limits the access to transplantation to a small number of patients each year. In this context, induction of cardiac regeneration in the damaged heart could represent an attractive therapeutic approach. This will only be possible if the pathways important for inducing repair and their associated regulatory mechanisms are identified.In the damaged heart, compensatory myocyte hypertrophy maintains cardiac output. Recent evidence suggests, however, that myocytes could be replaced continuously through a process involving replication, differentiation, senescence and death. Along these lines, resident cardiac stem cells have been identified. Together, this indicates that, akin of prototypic self-renewing tissues, the heart could possess the basic and necessary elements for tissue regeneration.The Notch pathway has crucial roles in the embryonic life of metazoans, and is essential during development of the cardiovascular system in mammals. It is also involved in regeneration of adult self-renewing tissues. We recently demonstrated that the Notch pathway is activated in the stressed adult heart. Notch1-receptor signaling takes place in cardiomyocytes and in cardiac precursors, and is activated secondary to stimulated expression of the Notch receptor ligand Jagged1 on the surface of cardiomyocytes. In cardiomyocytes, Notch controls maturation, limits the extent of the hypertrophic response and contribute to cell survival. In cardiac precursors, Notch prevents cardiogenic differentiation, favors proliferation, and facilitates the expansion of a transient amplifying cell compartment. These results suggest that controlled activation of the Notch pathway during the adaptation of the heart to stress should produce beneficial effects via induction of cardiac stem cell expansion, control of cardiogenesis, improvement of cardiomyocyte survival, and reduction of cardiac fibrosis. Therefore, we propose to test this hypothesis using different approaches in vitro and in vivo. In particular, we will use transgenic mouse models, in which the Notch pathway can be transiently or chronically activated, and conditional and inducible knockouts, in which the Notch pathway can be inhibited.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Cardiac dysfunction and impaired compensatory response to pressure overload in mice deficient in stem cell antigen-1.
Rosenblatt-Velin Nathalie, Ogay Sandy, Felley Allison, Stanford William L, Pedrazzini Thierry, Cardiac dysfunction and impaired compensatory response to pressure overload in mice deficient in stem cell antigen-1., in FASEB journal : official publication of the Federation of American Societies for Experimental Biolog, 26(1), 229-39.
Cardiac dysfunction and impaired compensatory response to pressure overload in mice deficient in stem cell antigen-1.
Rosenblatt-Velin Nathalie, Ogay Sandy, Felley Allison, Stanford William L, Pedrazzini Thierry, Cardiac dysfunction and impaired compensatory response to pressure overload in mice deficient in stem cell antigen-1., in FASEB journal : official publication of the Federation of American Societies for Experimental Biolog, 26(1), 229-39.
Cardiac lineage protein-1 (CLP-1) regulates cardiac remodeling via transcriptional modulation of diverse hypertrophic and fibrotic responses and angiotensin II-transforming growth factor β (TGF-β1) signaling axis.
Mascareno Eduardo, Galatioto Josephine, Rozenberg Inna, Salciccioli Louis, Kamran Haroon, Lazar Jason M, Liu Fang, Pedrazzini Thierry, Siddiqui M A Q, Cardiac lineage protein-1 (CLP-1) regulates cardiac remodeling via transcriptional modulation of diverse hypertrophic and fibrotic responses and angiotensin II-transforming growth factor β (TGF-β1) signaling axis., in The Journal of biological chemistry, 287(16), 13084-93.
Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice.
Shende Pankaj, Plaisance Isabelle, Morandi Christian, Pellieux Corinne, Berthonneche Corinne, Zorzato Francesco, Krishnan Jaya, Lerch René, Hall Michael N, Rüegg Markus A, Pedrazzini Thierry, Brink Marijke, Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice., in Circulation, 123(10), 1073-82.
Dietary obesity-associated Hif1α activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system.
Krishnan Jaya, Danzer Carsten, Simka Tatiana, Ukropec Josef, Walter Katharina Manuela, Kumpf Susann, Mirtschink Peter, Ukropcova Barbara, Gasperikova Daniela, Pedrazzini Thierry, Krek Wilhelm, Dietary obesity-associated Hif1α activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system., in Genes & development, 26(3), 259-70.
Differential effects of high-fat diet on myocardial lipid metabolism in failing and nonfailing hearts with angiotensin II-mediated cardiac remodeling in mice.
Pellieux Corinne, Montessuit Christophe, Papageorgiou Irène, Pedrazzini Thierry, Lerch René, Differential effects of high-fat diet on myocardial lipid metabolism in failing and nonfailing hearts with angiotensin II-mediated cardiac remodeling in mice., in American journal of physiology. Heart and circulatory physiology, 302(9), 1795-1805.
EH-myomesin splice isoform is a novel marker for dilated cardiomyopathy.
Schoenauer Roman, Emmert Maximilian Y, Felley Allison, Ehler Elisabeth, Brokopp Chad, Weber Benedikt, Nemir Mohamed, Faggian Giuseppe G, Pedrazzini Thierry, Falk Volkmar, Hoerstrup Simon P, Agarkova Irina, EH-myomesin splice isoform is a novel marker for dilated cardiomyopathy., in Basic research in cardiology, 106(2), 233-47.
Impact of salt on cardiac differential gene expression and coronary lesion in normotensive mineralocorticoid-treated mice.
Wang Qing, Domenighetti Andrea A, Schäfer Stephan C, Weber Johanns, Simon Alexandra, Maillard Marc P, Pedrazzini Thierry, Chen Ju, Lehr Hans-Anton, Burnier Michel, Impact of salt on cardiac differential gene expression and coronary lesion in normotensive mineralocorticoid-treated mice., in American journal of physiology. Regulatory, integrative and comparative physiology, 302(9), 1025-1033.
Isolation of cardiovascular precursor cells from the human fetal heart.
Gonzales Christine, Ullrich Nina D, Gerber Stefan, Berthonneche Corinne, Niggli Ernst, Pedrazzini Thierry, Isolation of cardiovascular precursor cells from the human fetal heart., in Tissue engineering. Part A, 18(1-2), 198-207.
Mapping genetic variants associated with beta-adrenergic responses in inbred mice.
Hersch Micha, Peter Bastian, Kang Hyun Min, Schüpfer Fanny, Abriel Hugues, Pedrazzini Thierry, Eskin Eleazar, Beckmann Jacques S, Bergmann Sven, Maurer Fabienne, Mapping genetic variants associated with beta-adrenergic responses in inbred mice., in PloS one, 7(7), 41032-41032.
Nitric oxide synthase 2 is required for conversion of pro-fibrogenic inflammatory CD133+ progenitors into F4/80+ macrophages in experimental autoimmune myocarditis.
Blyszczuk Przemyslaw, Berthonneche Corrine, Behnke Silvia, Glönkler Marcel, Moch Holger, Pedrazzini Thierry, Lüscher Thomas F, Eriksson Urs, Kania Gabriela, Nitric oxide synthase 2 is required for conversion of pro-fibrogenic inflammatory CD133+ progenitors into F4/80+ macrophages in experimental autoimmune myocarditis., in Cardiovascular research, 1(1), 1-1.
Small and long non-coding RNAs in cardiac homeostasis and regeneration.
Ounzain Samir, Crippa Stefania, Pedrazzini Thierry, Small and long non-coding RNAs in cardiac homeostasis and regeneration., in Biochimica et biophysica acta, 1(1), 1-1.
Stabilised beta-catenin in postnatal ventricular myocardium leads to dilated cardiomyopathy and premature death.
Hirschy Alain, Croquelois Adrien, Perriard Evelyne, Schoenauer Roman, Agarkova Irina, Hoerstrup Simon P, Taketo Makoto M, Pedrazzini Thierry, Perriard Jean-Claude, Ehler Elisabeth, Stabilised beta-catenin in postnatal ventricular myocardium leads to dilated cardiomyopathy and premature death., in Basic research in cardiology, 105(5), 597-608.

Associated projects

Number Title Start Funding scheme
163476 Regenerative therapy for heart disease via modulation of long noncoding RNAs 01.10.2015 Project funding
133825 Assessment of cell function using advanced flow cytometry 01.11.2011 R'EQUIP
114026 Pathways important for the mobilization of resident cardiac precursors cells in the diseased heart 01.10.2006 Project funding
143355 Role of the Notch pathway in cardiac multipotent mesenchymal stromal cells 01.10.2012 Project funding

Abstract

In the Western world, cardiovascular diseases account for fifty percents of hospitalizations and deaths. In high-income countries, the increasing average age of the population has altered the spectrum of cardiac diseases towards heart failure. Heart failure is a progressive disease that is initiated by a loss of functional cardiomyocytes. Heart transplant remains the ultimate therapy but the lack of donor organs limit the access to a few thousands of patients each year. In this context, therapies aimed at inducing cardiac repair could propose attractive alternatives. There are basically two approaches. First, cardiac stem cells are transferred into the damaged heart to produce a new myocardium. Second, endogenous cardiac stem cells are induced to proliferate and differentiate in situ to heal the heart. In both cases, however, the understanding of the precise molecular mechanisms controlling the expansion of the stem pools and those regulating cardiogenic differentiation is required. The Notch signaling pathway is implicated in adult tissue renewal and our recent experiments suggest that it may play a similar role in the heart. Therefore, the Notch pathway represents an interesting therapeutic target to obtain clinical benefit in heart failure patients.Our previous data demonstrate the importance of the Notch pathway in the adaptive response of the heart to stress. Signaling in Notch-receptor expressing cardiac cells is triggered by the Notch ligand Jagged1. These results suggest also that activation of the Notch pathway should produce beneficial effects in the damaged heart via induction of cardiac stem cell expansion, control of cardiogenesis, improvement of cardiomyocyte survival, and reduction of cardiac fibrosis. Therefore, we propose to test this hypothesis using different approaches in vitro and in vivo. In particular, we will use transgenic mouse models, in which the Notch pathway can be transiently or chronically activated, and conditional and inducible knockouts, in which the Notch pathway can be inhibited. Furthermore, we propose to investigate the role of the Notch pathway in the cardiogenic differentiation of embryonic stem cells, as prototypes of undifferentiated progenitors, and of cardiac stem cells isolated from the postnatal heart. The potential role of cardiomyocytes as accessory cells belonging to a Jagged1-expressing cardiac stem cell niche will be also investigated. Finally, the importance of microRNAs in the regulation of cardiogenesis by the Notch pathway will be evaluated.
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