Jagged1 intracellular domain-mediated inhibition of Notch1 signalling regulates cardiac homeostasis in the postnatal heart

Aims Notch1 signalling in the heart is mainly activated via expression of Jagged1 on the surface of cardiomyocytes. Notch controls cardiomyocyte proliferation and differentiation in the developing heart and regulates cardiac remodelling in the stressed adult heart. Besides canonical Notch receptor activation in signal-receiving cells, Notch ligands can also activate Notch receptor-independent responses in signal-sending cells via release of their intracellular domain. We evaluated therefore the importance of Jagged1 (J1) intracellular domain (ICD)-mediated pathways in the postnatal heart. Methods and results In cardiomyocytes, Jagged1 releases J1ICD, which then translocates into the nucleus and down-regulates Notch transcriptional activity. To study the importance of J1ICD in cardiac homeostasis, we generated transgenic mice expressing a tamoxifen-inducible form of J1ICD, specifically in cardiomyocytes. Using this model, we demonstrate that J1ICD-mediated Notch inhibition diminishes proliferation in the neonatal cardiomyocyte population and promotes maturation. In the neonatal heart, a response via Wnt and Akt pathway activation is elicited as an attempt to compensate for the deficit in cardiomyocyte number resulting from J1ICD activation. In the stressed adult heart, J1ICD activation results in a dramatic reduction of the number of Notch signalling cardiomyocytes, blunts the hypertrophic response, and reduces the number of apoptotic cardiomyocytes. Consistently, this occurs concomitantly with a significant down-regulation of the phosphorylation of the Akt effectors ribosomal S6 protein (S6) and eukaryotic initiation factor 4E binding protein1 (4EBP1) controlling protein synthesis. Conclusions Altogether, these data demonstrate the importance of J1ICD in the modulation of physiological and pathological hypertrophy, and reveal the existence of a novel pathway regulating cardiac homeostasi

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

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 cell

Cardiac mTOR complex 2 preserves ventricular function in pressure-overload hypertrophy

Mammalian target of rapamycin (mTOR), a central regulator of growth and metabolism, has tissue-specific functions depending on whether it is part of mTOR complex 1 (mTORC1) or mTORC2. We have previously shown that mTORC1 is required for adaptive cardiac hypertrophy and maintenance of function under basal and pressure-overload conditions. In the present study, we aimed to identify functions of mTORC2 in the heart.; Using tamoxifen-inducible cardiomyocyte-specific gene deletion, we generated mice deficient for cardiac rapamycin-insensitive companion of mTOR (rictor), an essential and specific component of mTORC2. Under basal conditions, rictor deficiency did not affect cardiac growth and function in young mice and also had no effects in adult mice. However, transverse aortic constriction caused dysfunction in the rictor-deficient hearts, whereas function was maintained in controls after 1 week of pressure overload. Adaptive increases in cardiac weight and cardiomyocyte cross-sectional area, fibrosis, and hypertrophic and metabolic gene expression were not different between the rictor-deficient and control mice. In control mice, maintained function was associated with increased protein levels of rictor, protein kinase C (PKC)βII, and PKCδ, whereas rictor ablation abolished these increases. Rictor deletion also significantly decreased PKCε at baseline and after pressure overload. Our data suggest that reduced PKCε and the inability to increase PKCβII and PKCδ abundance are, in accordance with their known function, responsible for decreased contractile performance of the rictor-deficient hearts.; Our study demonstrates that mTORC2 is implicated in maintaining contractile function of the pressure-overloaded male mouse heart

Cardiovascular Response to Beta-Adrenergic Blockade or Activation in 23 Inbred Mouse Strains

We report the characterisation of 27 cardiovascular-related traits in 23 inbred mouse strains. Mice were phenotyped either in response to chronic administration of a single dose of the β-adrenergic receptor blocker atenolol or under a low and a high dose of the β-agonist isoproterenol and compared to baseline condition. The robustness of our data is supported by high trait heritabilities (typically H2>0.7) and significant correlations of trait values measured in baseline condition with independent multistrain datasets of the Mouse Phenome Database. We then focused on the drug-, dose-, and strain-specific responses to β-stimulation and β-blockade of a selection of traits including heart rate, systolic blood pressure, cardiac weight indices, ECG parameters and body weight. Because of the wealth of data accumulated, we applied integrative analyses such as comprehensive bi-clustering to investigate the structure of the response across the different phenotypes, strains and experimental conditions. Information extracted from these analyses is discussed in terms of novelty and biological implications. For example, we observe that traits related to ventricular weight in most strains respond only to the high dose of isoproterenol, while heart rate and atrial weight are already affected by the low dose. Finally, we observe little concordance between strain similarity based on the phenotypes and genotypic relatedness computed from genomic SNP profiles. This indicates that cardiovascular phenotypes are unlikely to segregate according to global phylogeny, but rather be governed by smaller, local differences in the genetic architecture of the various strains

Mitochondrial ATP-sensitive potassium channels contribute to cardiac remodeling after myocardial infarction in rats

International audienc

Mitochondrial ATP-sensitive potassium channels contribute to cardiac remodeling after myocardial infarction in rats

International audienc

Mitochondrial ATP-sensitive potassium channels contribute to cardiac remodeling after myocardial infarction in rats

International audienc