Notch Signaling in Ischemic Damage and Fibrosis: Evidence and Clues from the Heart

Abstract

Notch signaling is a major intercellular coordination mechanism highly conserved throughout evolution. In vertebrates, Notch signaling is physiologically involved in embryo development, including mesenchymal cell commitment, formation of heart tissues and angiogenesis. In post-natal life, Notch signaling is maintained as a key mechanism of cell–cell communication and its dysregulations have been found in pathological conditions such as ischemic and fibrotic diseases. In the heart, Notch takes part in the protective response to ischemia, being involved in pre- and post-conditioning, reduction of reperfusion-induced oxidative stress and myocardial damage, and cardiomyogenesis. Conceivably, the cardioprotective effects of Notch may depend on neo-angiogenesis, thus blunting lethal myocardial ischemia, as well as on direct stimulation of cardiac cells to increase their resistance to injury. Another post-developmental adaptation of Notch signaling is fibrosis: being involved in the orientation of mesenchymal cell fate, Notch can modulate the differentiation of pro-fibrotic myofibroblasts, e.g., by reducing the effects of the profibrotic cytokine TGF-β. In conclusion, Notch can regulate the interactions between heart muscle and stromal cells and switch cardiac repair from a pro-fibrotic default pathway to a pro-cardiogenic one. These features make Notch signaling a suitable target for new cardiotropic therapies.

High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation

“…Importantly, the overexpression of the constitutively active Notch1-ICD, lacking EGF and Lin12/ Notch repeats, inhibited the effect of haloperidol and restored αSMA in fibroblasts. These data are also in line with multiple lines of evidence, supporting an antifibrotic role of the Notch pathway (80,81). Notch pathway components were found upregulated in models of cardiac, lung, skin, and liver fibrosis and chemical inhibition of the pathway invariably reduced the fibrotic signature, improving the outcome of the disease (82)(83)(84)(85).…”

Notch receptor expression in Trypanosoma cruzi‐infected human umbilical vein endothelial cells treated with benznidazole or simvastatin revealed by microarray analysis

“…However, since all its components are present, it can be activated after the appearance of specific stressors, which in the heart can be ischemia (Li et al, 2010). Furthermore, in some experimental models, Notch regulates fibrotic remodeling after ischemic insult (Nistri et al, 2017). It is postulated that during cardiac ischemic processes, such as acute myocardial infarction, there is a notch‐driven trend toward increasing cardiac progenitor cell differentiation.…”

“…In the injured myocardium, Notch has a regulatory role in the functional recovery of the ischemic myocardium, reactivating developmental processes in the adult. Under these circumstances, Notch reduces myocardial ischemia‐reperfusion injury by (i) limiting myocyte hypertrophy, (ii) enhancing myocyte survival, (iii) promoting precursor proliferation, (iv) controlling cardiogenic differentiation, and (v) reducing interstitial fibrosis (Nistri et al, 2017). Thus, pharmacological modulation of Notch signaling should decrease endothelial inflammation and enhance neovascularization and perfusion recovery for inflammatory and ischemic heart diseases (Rizzo et al, 2014).…”

Beyond cardiomyocyte loss: Role of Notch in cardiac aging

“…Furthermore, non-canonical ligands have been identified lacking the DSL domain and comprising a group of structurally diverse proteins that include integral and glycosylphosphatidylinositol (GPI)-linked membrane as well as secreted proteins (D'Souza et al, 2010). Nistri, Sassoli, & Bani, 2017). Consistently, the expression of components belonging to its signaling pathway has also been observed in myocardial biopsies from HF patients ).…”

“…Conversely, in the adult myocardium these cells lose the ability to proliferate and down‐regulate Notch signaling. Notch1 is reactivated in cardiomyocytes located in the MI border zone or in the overloaded myocardium, where it counteracts cardiomyocytes apoptosis and hypertrophy (Ferrari & Rizzo, ; Nistri, Sassoli, & Bani, ). Consistently, the expression of components belonging to its signaling pathway has also been observed in myocardial biopsies from HF patients (Ferrari & Rizzo, ).…”