The Notch Pathway and Sox17 Expression (p 215)
Notch suppresses Sox17 expression to inhibit vascular branching, report Lee et al.
Angiogenesis is essential for human development, growth and wound healing, but it can also be an undesirable process in some situations such as cancer, where it promotes tumor growth. Thus, understanding the mechanisms that increase or inhibit angiogenesis has high clinical significance. During angiogenesis, certain endothelial cells of the growing vessels become tip cells, which stretch out from the main channel and ultimately give rise to new branches. While it has been known for some time that Notch signaling suppresses tip cell formation, the downstream targets of Notch have not been identified. Now, Lee and colleagues report that Notch inhibits the expression of the transcription factor Sox17. They found that overexpression of Notch in endothelial cells led to specific downregulation of Sox17 protein, leaving the mRNA levels unaffected. Their results showed that Sox17 promoted tip cell formation in vitro, and that overexpression of Sox17 in mice increased both embryonic and post-natal vascular branching. However, the increase in postnatal branching was prevented by increased Notch signaling, indicating that Notch is an endogenous Sox17 suppressor. Interestingly, Sox17 is also an upstream regulator of Notch signaling during arterial differentiation, indicating that the interplay between these two factors is context-specific. Identification of factors that contribute to such contextual differences would be important for the development of future pro- or anti-angiogenesis therapies.
Benign HCM-Causing Mutation can Become Malignant (p 227)
An apparently benign mutation in β-MHC turns deadly in the presence of another β-MHC mutation, Blankenburg et al report.
Previous work has shown that approximately 40 percent of the cases of hypertrophic cardiomyopathy are caused by mutations in the gene encoding β-myosin heavy chain (β-MHC). Indeed, over 300 different mutations in β-MHC have been identified to be associated with the disease. While some mutations cause more severe symptoms than others, the severity of the V606M mutation, was unclear. Some individuals carrying the mutation have a normal life expectancy, while others die from heart failure before the age of 30. To investigate whether V606M influences, or is influenced by, other mutations in the β-MHC gene, Blankenburg made transgenic mice carrying mutant versions of human β-MHC. Mice that were heterozygous or homozygous for V606M exhibited no symptoms of hypertrophic cardiomyopathy. Mice that were heterozygous for the R453C mutations, however, displayed progressive hypertrophy and fibrosis, but lived a normal lifespan. Despite lack of symptoms with V606M alone, when crossed with R453C animals, the heterozygous mice had massive fibrosis, rapidly progressing hypertrophy and premature death. Although it remains unclear how the V606M mutation exacerbates disease in the presence of the R453C mutation, these findings suggest that patients found to be carrying one β-MHC mutation should be checked for others.
MiR-133 Targets β1AR Pathway (p 273)
MicroRNA-133 represses components of the β1-adrenergic signaling pathway, report Castaldi et al.
Hyperactivity of β-adrenergic signaling in cardiomyocytes is associated with heart disease. Indeed, β-blockers are commonly prescribed to treat congestive heart failure. One of the damaging effects of overt β-adrenergic signaling is the promotion of cardiomyocyte apoptosis. A microRNA called miR-133, on the other hand, suppresses cardiomyocyte apoptosis and tends to be expressed at reduced levels in cardiac hypertrophy patients. Castaldi and colleagues now link these findings by showing that miR-133 directly targets and suppresses the expression of the β1-adrenergic receptor (β1AR). Bioinformatic searches for candidate miR-133 targets revealed β1AR, adenylyl cyclase and other components of the signaling cascade, while in vitro experiments confirmed them as targets. In vivo experiments with transgenic mice that overexpressed miR-133 also confirmed the ability of miR-133 to suppress the expression of β1AR. And, importantly, when cardiac hypertrophy and heart failure were experimentally induced in these mice, they fared much better than control mice—cardiac function was preserved, remodeling of the myocardium was attenuated, and fibrosis was reduced. Based on these findings, the authors suggest that boosting the level of miR-133 in hypertrophy patients where it is reduced could be a novel strategy for the treatment of heart failure.
- © 2014 American Heart Association, Inc.