Embryonic process hardens hearts
Cardiac fibrosis and the resulting loss of heart muscle is a common consequence of heart attack and other types of heart disease. The scarring results from excessive deposition of extracellular matrix by fibroblasts, which in epithelial organs, come from epithelia by epithelial-mesenchymal transition (EMT). However, normal hearts have few fibroblasts, so the source of additional cardiac fibroblasts is unclear.
Eric Neilson, M.D., and colleagues at Harvard, investigated the notion that cardiac fibroblasts, not being able to derive from epithelia and EMT, appear following endothelial-mesenchymal transition (EndMT). Using transgenic mice developed by Neilson, the researchers discovered that mature endothelial cells indeed undergo EndMT, converting into cardiac fibroblasts that deposit the excess scar tissue. Additionally, administration of recombinant human bone morphogenic protein-7 inhibited EndMT and slowed the progression of fibrosis in two different cardiac models of fibrosis. The results, appearing in Nature Medicine, suggest a possible new treatment to halt cardiac fibrosis and mark the first observation of EndMT in an adult tissue.
— Melissa Marino
Carcinogens’ early actions
Cancer-causing chemicals are all around us — in the environment, in our food, in cigarette smoke. They may accumulate in breast tissue and pose particular risk to women, but little is known about the early responses of mammary cells to these chemicals.
Fritz Parl, M.D., Ph.D., and colleagues exposed normal human mammary epithelial cells (HMEC) to dietary and environmental carcinogens and screened a phage display library of antibodies to identify protein changes in response to the treatment. They report in Carcinogenesis that histone H3 — a protein that helps “package” DNA in the nucleus — has reduced lysine 4 methylation in treated HMEC compared to control cells. The investigators also found increased nuclear levels of a lysine-specific demethylase 1, which could account for the removal of histone H3 methyl groups.
The findings suggest that carcinogen-induced changes in histone H3 methylation may influence the expression of genes critical in early stage mammary carcinogenesis. Understanding such early responses could lead to improved diagnostic and therapeutic strategies.
— Leigh MacMillan
Diet link to memory deficits
While some rare types of Alzheimer's disease are caused by specific genetic mutations, most cases are sporadic, suggesting that potentially modifiable environmental or dietary factors are involved. Some studies have suggested links between dietary factors — like the amino acid homocysteine — and the cognitive deficits of Alzheimer's disease.
Michael McDonald, Ph.D., along with his graduate student Alexandra Bernardo and their colleagues at Tufts University, examined the role of diet-induced elevation of homocysteine on memory and amyloid plaque formation in an animal model of Alzheimer's disease.
They found that, after long-term maintenance on the treatment diet, transgenic mice showed significant impairments in spatial memory, while short-term working memory was not affected. The treatment diet also did not affect amyloid plaque accumulation, a pathological hallmark of the disease. The results, reported in the August issue of Neurobiology of Aging, suggest that disrupted homocysteine metabolism may contribute to some of the memory deficits of Alzheimer's disease.
— Melissa Marino
New roles on the rADAR
RNA editing changes the coding potential of mature mRNAs, which can affect the functional properties and biological activities of encoded proteins. The “RNA editor” ADAR2 is critical for normal nervous system function: mice lacking it develop seizures and die within weeks of birth.
To further explore ADAR2's physiological roles, Ronald Emeson, Ph.D., and colleagues developed transgenic mice overexpressing wild-type ADAR2 or a form of the enzyme that cannot edit target mRNAs. The investigators report Aug. 3 in the Journal of Biological Chemistry that both types of transgenic mice become obese as adults, and that this obesity results from overeating. Because both wild-type and inactive ADAR2 cause obesity in the transgenic mice, the investigators suggest that ADAR2 may have biological activities beyond RNA editing or that it may interfere with the actions of other double-stranded RNA binding proteins. The roles of RNA binding proteins, particularly in regulating feeding behavior and energy balance, are areas ripe for exploration.
— Leigh MacMillan
We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to: aliquots@vanderbilt.edu.
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