miR-218 Regulation of Slit-Robo Pathway (p 1336)
Small et al have discovered a microRNA that fine-tunes blood vessel development.
MicroRNAs (miRs) regulate gene expression by binding to target mRNAs and either preventing their translation or tagging them for degradation. Often, one miR can target multiple mRNAs encoding proteins that act in the same molecular pathway. Finding one miR might, thus, offer a means to control expression of an entire network of genes. Small et al decided to look for new miRs that might control cardiovascular development pathways. Within noncoding regions of the genes for Slit2 and Slit3, they found miR-218. Slit is a ligand for a receptor called Robo, and binding of Slit to Robo regulates vascular endothelial cell migration and blood vessel growth. The team discovered that miR-218 targeted and repressed the mRNAs for Robo1, Robo2, and other proteins that control Slit-Robo interactions. Knockdown of miR-218 raised the expression of the target genes and increased human endothelial cell migration. Knockdown of miR-218 in the retinas of newborn mice resulted in aberrant patterning and decreased the number and size of capillaries. The authors now want to check the involvement of miR-218 in various vascular pathologies and tumorogenesis, where regulating angiogenesis would be therapeutically desirable.
ACE Inhibition Impacts Monocyte Traffic After MI (p 1364)
Leuschner et al reveal how a drug for hypertension also helps to prevent heart failure.
Angiotensin II (Ang II) is an endogenous regulator of blood pressure. It is produced in the blood by angiotensin converting enzyme (ACE), and ACE inhibitors are well-established drugs for treating hypertension. Levels of Ang II increase after myocardial infarction (MI), and Ang II stimulates splenic monocyte mobilization (by binding to receptors on the monocytes). These monocytes enter the blood vessels and are recruited to the infarct to facilitate the healing process. Excessive inflammation can impair the healing process, however, and patients suffering MI often have elevated monocyte numbers and ongoing inflammatory processes as a result of preexisting atherosclerosis. Reducing monocyte recruitment to the infarct is, thus, desirable in such patients. Luckily, ACE inhibitors do just that, Leuschner et al now show. The ACE inhibitor, enalapril, reduced monocyte motility and recruitment, improved heart healing, and reduced potentially fatal ventricle remodeling in a mouse model of MI with preexisting atherosclerosis (ApoE−/− mice). Although the findings do not point to a new form of treatment, they do suggest that monitoring changes in monocyte numbers in post-MI patients might provide a means for assessing healing in the heart after infarction.
Age, Gender, and Cardiomyogenesis (p 1374)
Your heart cells are not as old as you, claim Kajstura et al. In fact by the time you are 100, your cardiomyocytes are no more than a few years old.
This seemingly paradoxical concept stems from calculations of Kajstura et al of cardiomyocyte turnover rates in relation to aging. The team analyzed postmortem heart tissue from men and women between the ages of 19 and 104 years who had died from causes other than cardiovascular conditions. By mathematical modeling, the team calculated that at the ages of 20, 60, and 100 years, myocytes in the male heart are replaced at rates of 7%, 12%, and 32% per year, respectively. For women, the rates were even higher: 10%, 14%, and 40%. These rates predict that between the ages of 20 and 100 years, the female heart replaces its entire myocyte compartment 15 times and the male heart does so 11 times. In old hearts, old cells were replaced with old cells, as defined by short telomeric DNA. Thus, as hearts age, replacement cells are less functional and progress to senescence and death more quickly, explaining the age-dependent increase in turnover rates. The team observed a small number of stem cells that retained their telomere length, even in aged hearts, however. Whether this pool of genetically youthful cells could be therapeutically activated to replace aged or damaged heart tissue will be an interesting possibility to investigate in the future.
Written by Ruth Williams
- © 2010 American Heart Association, Inc.