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

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

Genetic Spectrum of Idiopathic Restrictive Cardiomyopathy Uncovered by Next-Generation Sequencing.

BACKGROUND:Cardiomyopathies represent a rare group of disorders often of genetic origin. While approximately 50% of genetic causes are known for other types of cardiomyopathies, the genetic spectrum of restrictive cardiomyopathy (RCM) is largely unknown. The aim of the present study was to identify the genetic background of idiopathic RCM and to compile the obtained genetic variants to the novel signalling pathways using in silico protein network analysis. PATIENTS AND METHODS:We used Illumina MiSeq setup to screen for 108 cardiomyopathy and arrhythmia-associated genes in 24 patients with idiopathic RCM. Pathogenicity of genetic variants was classified according to American College of Medical Genetics and Genomics classification. RESULTS:Pathogenic and likely-pathogenic variants were detected in 13 of 24 patients resulting in an overall genotype-positive rate of 54%. Half of the genotype-positive patients carried a combination of pathogenic, likely-pathogenic variants and variants of unknown significance. The most frequent combination included mutations in sarcomeric and cytoskeletal genes (38%). A bioinformatics approach underlined the mechanotransducing protein networks important for RCM pathogenesis. CONCLUSIONS:Multiple gene mutations were detected in half of the RCM cases, with a combination of sarcomeric and cytoskeletal gene mutations being the most common. Mutations of genes encoding sarcomeric, cytoskeletal, and Z-line-associated proteins appear to have a predominant role in the development of RCM

Interaction network of proteins harboring RCM-associated genetic variants.

<p>For proteins with RCM-associated pathogenic and likely pathogenic variants (red boxed), variants of unknown significance (orange boxes) and rare SNPs (yellow boxes) a closely interconnected network was generated by manual curation of scientific literature. The interlinking proteins are shown as gray boxes. Green arrows, red lines with cross bars, green lines with filled circles, and blue lines indicate activation, inhibition, modulation of activity, and direct physical interactions, respectively.</p