Activation of Notch-Mediated Protective Signaling in the Myocardium

Abstract

Abstract-The Notch network regulates multiple cellular processes, including cell fate determination, development, differentiation, proliferation, apoptosis, and regeneration. These processes are regulated via Notch-mediated activity that involves hepatocyte growth factor (HGF)/c-Met receptor and phosphatidylinositol 3-kinase/Akt signaling cascades.

Signaling During Epicardium and Coronary Vessel Development

“…This study was based on an earlier publication showing that Notch protects the heart after myocardial injury by triggering a CM survival response mediated by activation of c-Met and Akt. 139 Using the CBF1Re x4 -EGFP line, these authors identify an EGFP ϩ /CD45 Ϫ /CD31 Ϫ cell population with a gene expression signature of multipotent stromal cells called Notch-activated epicardial-derived cells. These cells express musclerelated and epicardial genes and localize in the epicardium.…”

2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside protects murine hearts against ischemia/reperfusion injury by activating Notch1/Hes1 signaling and attenuating endoplasmic reticulum stress

“…The binding of the Notch1 ligand to its receptor triggers the γ-secretasemediated proteolytic cleavage of NICD, which then translocates into the nucleus, up-regulating its downstream target gene Hes1 [49,50] . Notch signaling is believed to play a key role in maintaining functional homeostasis in adult hearts, as has been shown in studies related to heart models, such as myocardial infarction, cardiac hypertrophy and failure [26,51] . Interestingly, as the myocardium matures to the adult hormonal and contractile state, endogenous Notch signaling levels decreases steadily in heart tissue [24,26] .…”

“…Notch signaling is believed to play a key role in maintaining functional homeostasis in adult hearts, as has been shown in studies related to heart models, such as myocardial infarction, cardiac hypertrophy and failure [26,51] . Interestingly, as the myocardium matures to the adult hormonal and contractile state, endogenous Notch signaling levels decreases steadily in heart tissue [24,26] . However, accumulating evidence has indicated that re-activation of Notch signaling could constitute an adaptive response to the increased survival rate or regenerate tissues following pathological stress.…”

“…In the heart, Notch signaling not only regulates embryonic cardiac development and differentiation [23] , but also stimulates proliferation of immature cardiomyocytes [24] and promotes quiescent cardiomyocytes to reenter the cell cycle [25] . Many studies have shown that the Notch1, NICD and the downstream target protein Hes1, which decrease in cardiomyocytes during cardiac postnatal development, are restored and activated in the adult injured myocardium [26] .…”

The therapeutic relevance of microRNA-199b in preclinical models of heart failure

“…Induction of Notch signaling takes place in the border zone and is associated with anti-hypertrophic, anti-fibrotic and pro-angiogenic responses in the adult myocardium. 38,40,42,43 Similarly, the elevated fibrosis observed in the border zone of MI-miRNA-199b transgenic hearts could be related to blunted Notch activity by inhibition of notch1 and jagged1 expression after cardiac restricted upregulation of miR-199b.…”