RasGRP3 and Diabetic Embryonic Vasculopathy (p 1199)
Randhawa et al suggest a means to protect embryos of diabetic mothers from developing vascular defects.
Babies born to diabetic mothers run a risk of having cardiovascular birth defects, and the severity of such defects correlates with maternal blood glucose levels. The molecular pathway from high maternal blood sugar to abnormal fetal vascular development is murky, but certain molecular players, including diacylglycerol and RasGRP3, are suspected to be involved. RasGRP3 is an intracellular signaling molecule expressed in developing blood vessels and is also activated by diacylglycerol (a cellular membrane lipid). Furthermore, diacylglycerol is known to be elevated in diabetic patients and animals. Randhawa et al have now put the pieces together and shown that diacylglycerol activation of embryonic RasGRP3 is needed for the diabetes-associated vascular defects to manifest. Embryos that lacked RasGRP3 were protected from the damaging diabetic environment. Overt activation of RasGRP3 caused endothelial cells in culture to exhibit aberrant cell migration in response to endothelin-1. This faulty migration may be the cause of the defective vascular development, says the team. Importantly, they add, RasGRP3 presents itself as a possible target for protective therapy in diabetic pregnancies.
Generation of New Cardiac Myocytes (p 1226)
Progenitor cell proliferation is the source of new myocytes in injured mammalian hearts, say Angert et al.
It has been traditionally thought that after injury, the adult mammalian heart is unable to regenerate myocytes to adequately restore function. Instead, fibrotic scar tissue forms, and myocytes enlarge in an attempt to compensate for reduced contractility. The reduced functionality puts the heart under stress and, in many cases, leads to heart failure and death. Emerging evidence, however, challenges this dogma and indicates that adult cardiomyocytes can regenerate, albeit in small numbers; this has prompted speculation that if the process could be therapeutically promoted, repair could be improved. Angert et al decided to investigate the source of these new myocytes. They injured mouse hearts by infusing a chemical called isoproterenol for ten days and looked for regenerating cells using a marker (BrdU), which incorporates into DNA during cell replication. During and immediately after injury, about 20% of heart cell nuclei contained BrdU. Very few of these cells were myocytes, however. Most were cardiac progenitor cells. Later in recovery (one to four weeks), myocytes containing BrdU were apparent. The most straightforward explanation, say the authors, is that progenitors rapidly divide at the stage of injury and, later, differentiate into cardiomyocytes. Boosting progenitor proliferation might, therefore, be a method for improving adult heart regeneration.
Pim-1 and Diabetic Cardiomyopathy (p 1238)
Promoting Pim-1 activity can protect against diabetic cardiomyopathy, report Katare et al.
Cardiomyopathy, and subsequent heart failure, is all too common in patients with diabetes, but the mechanisms of pathology are not entirely understood. Katare et al postulated that a protein kinase called Pim-1 could be involved, because it is known to promote cardiomyocyte survival and to be down-regulated during diabetic cardiomyopathy. Here, the team showed that as cardiomyopathy progresses in diabetic mice, inhibitors of Pim-1 activity—namely, the phosphatase PP2A and the microRNA miR-1—increased in activity, concomitant with an increase in cardiomyocyte apoptosis. Importantly, inhibiting miR-1, or increasing expression of Pim-1, led to an increase in cardiomyocyte survival in vitro. In diabetic mice, systemic injection of Pim-1 attached to a heart-homing vector (AAV9) led to heart-specific expression of Pim-1. In turn, this improved cardiac function, prevented left ventricle dilation and heart failure, and improved survival of cardiac progenitor cells (progenitor cells had been shown previously to be exhausted in diabetic cardiomyopathic hearts). In conclusion, increasing Pim-1 activity in the heart could be a useful therapeutic approach for preventing heart failure in diabetes.
Written by Ruth Williams
- © 2011 American Heart Association, Inc.