Abstract
Dysregulation of the Notch pathway is implicated in the pathophysiology of cardiovascular diseases (CVDs), but, as of today, therapies based on the re-establishing the physiological levels of Notch in the heart and vessels are not available. A possible reason is the context-dependent role of Notch in the cardiovascular system, which would require a finely tuned, cell-specific approach. MicroRNAs (miRNAs) are short functional endogenous, non-coding RNA sequences able to regulate gene expression at post-transcriptional levels influencing most, if not all, biological processes. Dysregulation of miRNAs expression is implicated in the molecular mechanisms underlying many CVDs. Notch is regulated and regulates a large number of miRNAs expressed in the cardiovascular system and, thus, targeting these miRNAs could represent an avenue to be explored to target Notch for CVDs. In this Review, we provide an overview of both established and potential, based on evidence in other pathologies, crosstalks between miRNAs and Notch in cellular processes underlying atherosclerosis, myocardial ischemia, heart failure, calcification of aortic valve, and arrhythmias. We also discuss the potential advantages, as well as the challenges, of using miRNAs for a Notch-based approach for the diagnosis and treatment of the most common CVDs.
Highlights
The Notch pathway, a highly conserved modality of intercellular signaling, is crucial for the development and postnatal homeostasis of the cardiovascular system (MacGrogan et al, 2018)
Many miRNAs have been identified with the potential to treat and diagnose cardiovascular diseases (CVDs) [for details the reader is referred to Nouraee and Mowla (2015) and Lucas et al (2018)]. The aim of this Review is to provide an overview of the existing knowledge on miRNAs-mediated Notch regulation in miRNAs Regulating Notch in Cardiovascular Disease atherosclerosis, myocardial ischemia, heart failure, calcific aortic valve disease, and arrhythmias, and to propose investigations in the cardiovascular setting on crosstalks between miRNAs and Notch signaling reported in other pathologies, such as cancer and cerebral stroke
The Jagged1/Notch3 axis promotes the vascular smooth muscle cells (VSMCs) contractile phenotype (Domenga et al, 2004; Doi et al, 2006; Boscolo et al, 2011) and NF-kB-mediated inhibition of Notch3 favors the transition from a contractile to a secretory, pro-inflammatory phenotype (Clement et al, 2007). Consistent with these studies, we demonstrated that in rat aortic VSMCs, cholesterol accumulation favored the reduction of contractile phenotype and the induction of pro-inflammatory markers in association with low levels of Jagged1 and high levels of Dll4 (Aquila et al, 2017)
Summary
The Notch pathway, a highly conserved modality of intercellular signaling, is crucial for the development and postnatal homeostasis of the cardiovascular system (MacGrogan et al, 2018). The above described modality of action of Notch is commonly defined as “canonical,” there is accumulating evidence of the existence of a “non-canonical” Notch pathway which is activated in the absence of “canonical” ligands (Delta-like 1, 3, 4, and Jagged 1, 2), independent of γ-secretase cleavage and leading to the formation of NICD that can interact with nuclear proteins different from RBPJ and with cytoplasmic proteins. Through the “non-canonical signaling,” Notch modulates pathways such as Wnt/β-catenin, mammalian target of the rapamycin 2 complex (mTORC2)/Akt, Nuclear Factor kappa B (NF-κB), IkB kinase (IKK)-α/β and phosphatase and tensin homolog (PTEN)induced kinase (PINK1) on mitochondria which, after binding NICD, activates mTORC2/Akt pathway, promoting cell survival (Ayaz and Osborne, 2014) (Figure 1A)
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