Inhibition of the Notch1 pathway induces peripartum cardiomyopathy

Abstract

Increased expression and activity of cardiac and circulating cathepsin D and soluble fms‐like tyrosine kinase‐1 (sFlt‐1) have been demonstrated to induce and promote peripartum cardiomyopathy (PPCM) via promoting cleavage of 23‐kD prolactin (PRL) to 16‐kD PRL and neutralizing vascular endothelial growth factor (VEGF), respectively. We hypothesized that activation of Hes1 is proposed to suppress cathepsin D via activating Stat3, leading to alleviated development of PPCM. In the present study, we aimed to investigate the role of Notch1/Hes1 pathway in PPCM. Pregnant mice between prenatal 3 days and postpartum 3 weeks were fed with LY‐411575 (a notch inhibitor, 10 mg/kg/d). Ventricular function and pathology were evaluated by echocardiography and histological analysis. Western blotting analysis was used to examine the expression at the protein level. The results found that inhibition of Notch1 significantly promoted postpartum ventricular dilatation, myocardial hypertrophy and myocardial interstitial fibrosis and suppressed myocardial angiogenesis. Western blotting analysis showed that inhibition of Notch1 markedly increased cathepsin D and sFlt‐1, reduced Hes1, phosphorylated Stat3 (p‐Stat3), VEGFA and PDGFB, and promoted cleavage of 23k‐D PRL to 16‐kD PRL. Collectively, inhibition of Notch1/Hes1 pathway induced and promoted PPCM via increasing the expressions of cathepsin D and sFlt‐1. Notch1/Hes1 was a promising target for prevention and therapeutic regimen of PPCM.

Suppression of Inflammatory Cardiac Cytokine Network in Rats with Untreated Obesity and Pre-Diabetes by AT2 Receptor Agonist NP-6A4

“…At the same time NP-6A4-AT2R signaling increases expression of Notch1 and EPO that promote cardiac repair. Notch1 signaling is activated in response to myocardial injury and is involved in suppression of cardiomyocyte apoptosis, cardiac repair and regeneration (Li et al, 2010;Yu and Song, 2014;Zhu et al, 2020). Erythropoietin (EPO) increases myocardial performance and induces cardiac repair after myocardial infarction (Santhanam et al, 2010;Zafiriou et al, 2014).…”

“…Cardiac levels of two molecules implicated in cardiac repair, Erythropoietin (EPO) (Santhanam et al, 2010;Zafiriou et al, 2014)) and Notch1 (Yu and Song 2014;Zhu et al, 2020;Li et al, 2021) were significantly increased by NP-6A4 in ZO rat heart (Figure 5A). Thus, NP-6A4 increased the expression of at least three cardioprotective molecules in the ZO rat heart, namely, AT2R, EPO and Notch1.…”

Animal Models of Cardiovascular Complications of Pregnancy

“…Treatment of pregnant wild-type mice during the last 3 days of gestation and first 3 weeks postpartum with an inhibitor of γ-secretase, which is required to activate Notch1 and normal angiogenesis, led to systolic cardiac failure, accompanied by blunted angiogenesis and lower circulating levels of cathepsin D and of sFlt1. 127 The study did not elucidate if γ-secretase inhibition elicits this cardiac phenotype primarily by acting on endothelial cells (where Notch1 plays a strong role) versus in cardiomyocytes (where cathepsin D is regulated) versus the placenta (the primary source of sFlt1 during pregnancy). Known effects of γ-secretase inhibition beyond suppression of Notch1 may also have contributed to the phenotype.…”

The Role of the Notch Signaling Pathway in Recovery of Cardiac Function after Myocardial Infarction

“…Notch signaling may inhibit CMC hypertrophy [ 5 , 44 ]. Thus, it has been shown that the inhibition of the Notch1-Hes1 axis by a γ-secretase inhibitor (LY-411575) results in the increased expression of hypertrophic genes (ANP, BNP and β-MHC) [ 45 ]. “Created with BioRender.com”.…”