Modulation of Angiogenesis by miR-10 (p 1421)
MicroRNA-10 is a potent regulator of angiogenesis, report Hassel et al.
The formation of new blood vessels–angiogenesis–is not restricted to embryogenesis. Indeed, vascular networks continuously sprout new branches and prune others to meet the changing oxygen demands of adult tissue. While this is a normal physiological process it also contributes to pathological states such as cancer. Both physiological and pathological angiogenesis are regulated by a compendium of transcription factors, signals, and receptors. And now Hassel et al add microRNA-10 (miR-10) to this list. MicroRNAs are short non-coding RNAs that suppress the expression of target messenger RNAs and Hassel et al have discovered that miR-10 suppresses the mRNA of FLT1—a cell surface protein that binds and sequesters the angiogenesis-promoting protein VEGF. Human endothelial cells that lacked miR-10 showed increased FLT1 levels and, as a consequence, decreased binding of VEGF to its receptor. Moreover, in comparison with control endothelial cells, miR-10-lacking cells were less capable of developing into branching vessel structures in vitro. Previous studies have shown that miR-10 is highly conserved across vertebrates and the authors demonstrate that zebrafish embryos lacking miR-10 have impaired blood vessel formation. Based on this work, the authors suggest that miR-10 could be a powerful new target for finely tuning angiogenesis in a variety of disease settings.
Stem Cell Factor Therapy (p 1434)
Increased local expression of SCF recruits progenitor cells to damaged hearts and boosts repair, report Yaniz-Galende et al.
When the heart tissue is damaged by a myocardial infarction, cardiac progenitor cells are recruited to the injury site to aid repair. But it is all too clear from the number of heart attack survivors suffering from hypertrophy and heart failure, that this repair process is limited. Yaniz-Galende et al wondered whether this limitation could be overcome by increasing the number of progenitor cells to the site of injury. They induced myocardial infarctions in rats and then injected the peri-infarct area with adenovirus vectors carrying the gene for stem cell factor (SCF). SCF is the ligand for the cell-surface receptor c-kit, expressed on progenitor cells, and it both recruits progenitor cells and promotes their proliferation. Sure enough, one week after the infarctions, SCF-overexpressing hearts had recruited higher numbers of progenitor cells. And a couple of months after that, the SCF hearts exhibited, decreased fibrosis, less left ventricular hypertrophy, and, importantly, improved function. The rats themselves also survived longer. The authors suggest that a similar type of gene therapy approach might be possible as a cardiac regenerative strategy in human patients.
Stress Accelerates Reverse Cholesterol Transport (p 1459)
A little stress can be a good thing, say Silvennoinen et al, who show that stressed mice excrete more cholesterol.
Stress has long been associated with an increased risk for cardiovascular disease. In particular, emotional stress is positively associated with atherosclerosis. However, there is no known physiological mechanism linking the two. A key process affecting atherogenesis is the uptake and secretion of cholesterol both by macrophages in the artery walls, and by the liver and intestine. Silvennoinen et al investigated how psychological stress affected this process by tracing the movements of radioactively labeled cholesterol in mice that had been physically restrained for 3 hours. Unexpectedly, they found that the stress markedly increased the amount of cholesterol excreted into the intestinal lumen, and reduced cholesterol absorption. Stress decreased the expression of NPC1L1—a protein responsible for intestinal cholesterol uptake—by increasing expression of PPAR—a known suppressor of NCP1L1. Injecting non-stressed mice with the stress hormone corticosterone mimicked these effects. The authors did not determine whether this surprising short-term stress effect could affect long-term atherosclerosis, but if so, and if the finding holds true in humans, it may guide the design of novel drugs for treating atherosclerosis.
- © 2012 American Heart Association, Inc.