Blockade of RBP-J-Mediated Notch Signaling Pathway Exacerbates Cardiac Remodeling after Infarction by Increasing Apoptosis in Mice

Abstract

Background Ischemic heart disease (IHD) is the major cause of death in patients with cardiovascular disease. Cardiac remodeling is a common pathological change following myocardial infarction (MI), and cardiomyocyte apoptosis plays a key role in this change. Transcription factor recombination signal-binding protein-J (RBP-J)-mediated Notch signaling pathway has been implicated in several inherited cardiovascular diseases, including aortic valve diseases, but whether the RBP-J-mediated Notch signaling pathway plays a role in cardiomyocyte apoptosis after MI is unclear. Method We crossed RBP-Jfl/fl mice and Myh6-Cre/Esr1 transgenic mice to delete RBP-J in vivo and to partly inhibit the canonical Notch signaling pathway. MI was induced in mice by permanent ligation of the left anterior descending coronary artery followed by the knockout of RBP-J. Cardiac function and morphology were assessed by echocardiography and histological analysis 4 weeks after infarction. In addition, the expression and regulation of apoptosis-related molecules were examined by real time PCR and western blot. Results RBP-J knockout decreased the survival rate and deteriorated post-MI remodeling and function in mice, and this effect was associated with increased cardiomyocyte apoptosis. The potential mechanisms might be related to the downregulated expression of bcl-2, upregulated expression of bax, and cleaved-caspase 3 to exacerbate cardiomyocyte apoptosis. Conclusion These findings show that the RBP-J-mediated Notch signaling pathway in cardiomyocytes limits ventricular remodeling and improves cardiac function after MI. The RBP-J-mediated Notch signaling pathway has a protective role in cardiomyocyte apoptosis following cardiac injury.

Identification of key microRNAs and the underlying molecular mechanism in spinal cord ischemia-reperfusion injury in rats

“…RBPJ-deficient pericytes induced pathogenic transformation of the vasculature resembling CCMs at the morphological and molecular level and contribute to bigger stroke lesions upon ischemic insult ( Diéguez-Hurtado et al, 2019 ). He et al indicated that the RBPJ-mediated Notch signaling might be involved in reducing cardiomyocyte apoptosis after myocardial infarction ( He et al, 2018 ). Considering previous studies and the results in this study, miR-3568 might be involved in the apoptosis in SCII.…”

<p><em>NR5A2</em> Promotes Cell Growth and Resistance to Temozolomide Through Regulating Notch Signal Pathway in Glioma</p>

“…NOTCH1. 29 hES, 30 Cyclin D1 31 and MMP2 32 were proved to promote Notch signaling pathway activation, while p21, 33 cleaved caspase-3, 34 cleaved PARP 35 and E-cadherin 36 were reported to interdict it. To verify our prediction, the expression of these above proteins that related to Notch signaling pathway, in U138 and U251 cells that after transfection were detected using Western blot.…”

Identification of monocyte-associated genes as predictive biomarkers of heart failure after acute myocardial infarction

“…In line with these characteristics, functional enrichment analysis in our study showed that genes in HF-related modules mainly participated in inflammatory/inflammation-associated response, immune response, apoptosis and cell cycle transition. The corresponding pathways were Notch signaling pathway, chemokine signaling pathway, MAPK signaling pathway, TNF signaling pathway, cell cycle, antigen processing and presentation, Th17 cell differentiation, DNA replication, all of which play an importantly regulatory role in the cardiac remodeling and consequent HF [ 8 , 9 , 31 , 32 ]. These results suggested that AMI patients with developing HF might have more serious inflammation, immunity and apoptosis in infarct zones than whom without HF.…”