The Notch pathway controls fibrotic and regenerative repair in the adult heart.

Abstract

AIMS:

In the adult heart, Notch signalling regulates the response to injury. Notch inhibition leads to increased cardiomyocyte apoptosis, and exacerbates the development of cardiac hypertrophy and fibrosis. The role of Notch in the mesenchymal stromal cell fraction, which contains cardiac fibroblasts and cardiac precursor cells, is, however, largely unknown. In the present study, we evaluate, therefore, whether forced activation of the Notch pathway in mesenchymal stromal cells regulates pathological cardiac remodelling.

METHODS AND RESULTS:

We generated transgenic mice overexpressing the Notch ligand Jagged1 on the surface of cardiomyocytes to activate Notch signalling in adjacent myocyte and non-myocyte cells. In neonatal transgenic mice, activated Notch sustained cardiac precursor and myocyte proliferation after birth, and led to increased numbers of cardiac myocytes in adult mice. In the adult heart under pressure overload, Notch inhibited the development of cardiomyocyte hypertrophy and transforming growth factor-β/connective tissue growth factor-mediated cardiac fibrosis. Most importantly, Notch activation in the stressed adult heart reduced the proliferation of myofibroblasts and stimulated the expansion of stem cell antigen-1-positive cells, and in particular of Nkx2.5-positive cardiac precursor cells.

CONCLUSIONS:

We conclude that Notch is pivotal in the healing process of the injured heart. Specifically, Notch regulates key cellular mechanisms in the mesenchymal stromal cell population, and thereby controls the balance between fibrotic and regenerative repair in the adult heart. Altogether, these findings indicate that Notch represents a unique therapeutic target for inducing regeneration in the adult heart via mobilization of cardiac precursor cells.

• Authors: Mohamed Nemir, Mélanie Metrich, Isabelle Plaisance, Mario Lepore, Steeve Cruchet, Corinne Berthonneche, Alexandre Sarre, Freddy Radtke, Thierry Pedrazzini
• Journal: European heart journal (Eur Heart J) Vol. 35 Issue 32 Pg. 2174-85 (Aug 21 2014) ISSN: 1522-9645 [Electronic] England
• PMID: 23166366 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2012.

Chemical References

• Calcium-Binding Proteins
• Intercellular Signaling Peptides and Proteins
• JAG1 protein, human
• Jag1 protein, mouse
• Jagged-1 Protein
• Membrane Proteins
• Receptors, Notch
• Serrate-Jagged Proteins
• Transforming Growth Factors
• mTOR protein, mouse
• TOR Serine-Threonine Kinases
• PTEN Phosphohydrolase
• Pten protein, mouse

Topics

• Animals
• Calcium-Binding Proteins (metabolism)
• Cardiomegaly (physiopathology, therapy)
• Cell Proliferation (physiology)
• Cell Size
• Constriction
• Fibrosis (metabolism)
• Heart (physiology)
• Humans
• Intercellular Signaling Peptides and Proteins (metabolism)
• Jagged-1 Protein
• Membrane Proteins (metabolism)
• Mice, Transgenic
• Myocytes, Cardiac (cytology, metabolism)
• PTEN Phosphohydrolase (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Receptors, Notch (physiology)
• Regeneration
• Serrate-Jagged Proteins
• Signal Transduction (physiology)
• TOR Serine-Threonine Kinases (metabolism)
• Transforming Growth Factors (metabolism)
• Ventricular Remodeling (physiology)