Cy-3-G, Gut Flora, and RCT (p 967)
Wang et al discover that microbes in the gut convey the atherosclerosis-busting benefits of a flavonoid found in fruit.
It is well known that red wine and fruits rich in color significantly lower the risk for atherosclerosis. This is, in large part due to their high levels of flavonoids, such as Cy-3-G. The maximum levels of this flavanoid detected in human blood, however, are far less than those necessary to reduce atherosclerotic risk. It is therefore thought that metabolites of Cy-3-G provide the main benefit—indeed, PCA, a known CY-3-G metabolite, has been shown to have anti-atherosclerotic effects. Wang et al have now discovered not only where PCA production happens in the body, but how it reduces atherosclerosis. While mice fed Cy-3-G produced high levels of plasma PCA, if given antibiotics, their plasma PCA levels were no longer detectable. If, however, these antibiotic-treated mice then had their gut microbes restored, their plasma PCA levels rebounded, confirming that gut microbes are essential for the production of PCA. In terms of mechanism, the team found that PCA reduced levels of miR-10b, a macrophage microRNA that suppresses cholesterol efflux-promoting proteins. More PCA thus induces more cholesterol efflux. The authors suggest that in addition to the manipulation of gut microbes, targeted repression of macrophage miR-10b might also be a viable treatment for atherosclerosis.
Mitofusins in Early Postnatal Life (p 1012)
In early postnatal development, reorganization of mitochondria in the heart is crucial for heart function, report Papanicolaou et al.
When the circulatory system of a newborn mammal switches from placental to pulmonary oxygenation, the heart undergoes a series of dramatic changes. Myocytes not only cease to proliferate, undergo hypertrophy, and reorganize their cytoskeletons, but their mitochondria change shape, thicken, lose mobility and align with myofibrils and the sarcoplasmic reticulum. Papanicolaou et al have now discovered that mitofusin proteins can promote this remodeling of the postnatal heart, by regulating mitochondrial fusion, morphology, and dynamics. Mouse fetuses specifically engineered to lose Mitofusin 1 and 2 from their hearts at mid-gestation were as healthy as wild type fetuses, initially. But soon after birth, their hearts exhibited mitochondrial and structural abnormalities and the mice died approximately 1 to 2 weeks later. The engineered mice did actually develop large numbers of mitochondria but, unlike those of the wild type mice, they were spherical and either very large or very small. In wild type mice, the expression of Mitofusins 1 and 2 increased at birth, confirming the importance of these proteins in postnatal mitochondrial and cardiac function.
GRK5 in Pathological Hypertrophy (p 1048)
Inhibiting GRK5 kinase could slow down hypertrophy progression, suggest Gold et al.
Cardiac hypertrophy can be caused by, among other things, high blood pressure or post-infarction cardiac injury. And if these causal factors are not resolved, hypertrophy can ultimately lead to heart failure and eventual death. A significant pathological step in the progression of hypertrophy to heart failure is the increased expression of pro-hypertrophy genes. Gene regulators called histone deacetylases (HDACs) are known to repress such genes, but Gold et al previously found that over-expressing the kinase G protein-coupled receptor kinase 5 (GRK5) leads to the phosphorylation and inhibition of these HDACs. However, whether endogenous GRK5 could influence hypertrophy was unknown. Thus, Gold et al examined mice in which GRK5 had been genetically deleted—from the whole animal and from the heart tissue only. They found that both types of deletion significantly lessened the development of induced hypertrophy. Compared with their wild type counterparts, the genetically engineered mice showed reduced levels of phosphorylated HDACs and reduced expression of pro-hypertrophy genes. They also had smaller hearts and superior cardiac function. The authors conclude that inhibiting GRK5 activity in the heart could slow hypertrophy progression, thus reducing the risk of heart failure and death.
Written by Ruth Williams
- © 2012 American Heart Association, Inc.