The Notch pathway: a novel therapeutic target for cardiovascular diseases?

ABSTRACT

Introduction: The Notch pathway is involved in determining cell fate during development and postnatally in continuously renewing tissues, such as the endothelium, the epithelium, and in the stem cells pool. The dysregulation of the Notch pathway is one of the causes of limited response, or resistance, to available cancer treatments and novel therapeutic strategies based on Notch inhibition are being investigated in preclinical and clinical studies in oncology. A large body of evidence now shows that the dysregulation of the Notch pathway is also involved in the pathophysiology of cardiovascular diseases (CVDs).

Areas covered: This review discusses the molecular mechanisms involving Notch which underlie heart failure, aortic valve calcification, and aortic aneurysm.

Expert opinion: Despite the existence of preventive, pharmacological and surgical interventions approaches, CVDs are the first causes of mortality worldwide. The Notch pathway is becoming increasingly recognized as being involved in heart failure, aortic aneurysm and aortic valve calcification, which are among the most common global causes of mortality due to CVDs. As already shown in cancer, the dissection of the biological processes and molecular mechanisms involving Notch should pave the way for new strategies to prevent and cure these diseases.

KEYWORDS:

• Notch
• heart failure
• aortic aneurysm
• aortic valve calcification
• endothelial dysfunction
• cardiotoxicity
• macrophages
• Dll4
• Notch1

Article Highlights

• The Notch pathway plays pivotal roles in the cardiovascular system, both during the development and postnatal life

• The role of Notch in congenital cardiovascular diseases is well established

• Dysregulated Notch pathway is increasingly linked to heart failure, aortic aneurysm, and aortic valve calcification

• Cardiovascular diseases and cancer share risk factors and underlying molecular pathways, including the Notch signaling

• The dysregulation of Notch in solid tumors and leukemias has been long investigated and clinical trials targeting Notch in cancer are ongoing

• The accumulated experience of almost 30 years on the targeting of Notch for cancer therapy should expedite the development of novel Notch-based therapeutic approaches for cardiovascular diseases

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This study was funded by Fondazione Annamaria Sechi per il Cuore to L Marracino, Fondo Ateneo per la Ricerca 2017 to P Rizzo, and the Russian Science Foundation 18-14-00152 to A Malaschicheva.