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Inhibition of the Notch1 pathway induces peripartum cardiomyopathy
- Source :
- Journal of Cellular and Molecular Medicine
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
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.
- Subjects :
- 0301 basic medicine
Peripartum cardiomyopathy
Angiogenesis
PRL
Cathepsin D
sFlt1
Mice
chemistry.chemical_compound
0302 clinical medicine
Pregnancy
Receptor, Notch1
PDGFB
Ventricular Remodeling
Vascular endothelial growth factor
Blot
Vascular endothelial growth factor A
Echocardiography
030220 oncology & carcinogenesis
embryonic structures
Molecular Medicine
Original Article
Female
Disease Susceptibility
Cardiomyopathies
Signal Transduction
endocrine system
medicine.medical_specialty
PPCM
Cardiomegaly
03 medical and health sciences
Internal medicine
Peripartum Period
medicine
Animals
Notch1
business.industry
Membrane Proteins
Original Articles
Cell Biology
medicine.disease
Fibrosis
Prolactin
Disease Models, Animal
030104 developmental biology
Endocrinology
chemistry
Proteolysis
business
Biomarkers
Subjects
Details
- ISSN :
- 15824934 and 15821838
- Volume :
- 24
- Database :
- OpenAIRE
- Journal :
- Journal of Cellular and Molecular Medicine
- Accession number :
- edsair.doi.dedup.....f0335f714110a62d26f1758cba57c9b9
- Full Text :
- https://doi.org/10.1111/jcmm.15423