Induction of Cardiomyocytes by Gene Transfer (p 1147)
Injecting three transcription factors into infarcted mouse hearts can convert fibroblasts into cardiomyocytes, report Ingawa et al.
After a myocardial infarction, fibroblasts in the heart proliferate and form a tough fibrous scar. Unfortunately, in the long-term this immediate wound response can have detrimental effects on the heart. Scarring leads to reduced contractility and elasticity, forcing the heart to work harder. This can ultimately lead to heart failure and death. But what if there was a way to convert the scar tissue into functional cardiomyocytes? A number of recent reports suggest that this might in fact be possible. Inagawa et al, for example, found that injecting infarcted mouse hearts with retroviruses containing three transcription factors—Gata4, Mef2a and Tbx5—could convert a small percentage of the fibroblast cells into cells that expressed cardiomyocyte proteins. The team did not investigate whether the converted cells exhibited cardiomyocyte function, or indeed conveyed improved heart function in the mice—because the cell conversion rates were too low to provide meaningful results. However, the study does provide preliminary support for the concept of direct in vivo cell conversion. This proof-of-principle work can be built upon in the future to develop better regenerative approaches to heart repair.
eNOS Prevents Obesity (p 1176)
Could we really eat what we want and stay thin? A study by Sansbury et al reveals that boosting levels of eNOS prevents obesity in over-fed mice.
Endothelial nitric oxide synthase (eNOS) is an enzyme that produces the potent vasodilator nitric oxide. In humans, impaired vasodilation and insulin resistance are both associated with obesity, while in animal models, a lack of eNOS induces insulin resistance and impairs fat metabolism. What hasn’t been clear, however, was whether an increase of eNOS could enhance fat metabolism and perhaps even prevent obesity and insulin resistance. Sansbury et al examined genetically engineered mice that over-express eNOS and found that when given a high-fat diet, the animals gained only about half as much weight as their wildtype counterparts. The svelte engineered mice were eating the same amount, even exercising the same amount, but burning more fat. They maintained a higher baseline metabolic activity and their fatty tissues did not show the adipocyte expansion seen in wildtype animals. Instead the mice showed a significant increase in the number and activity of mitochondria in the adipose tissue. The high fat diet did induce insulin resistance in both the engineered and wildtype mice, however. Further insight into the pathways affected by eNOS could aid the development of anti-obesity therapies, suggest the authors.
Neuro-immune Modulation is Pro-inflammatory in SHR (p 1190)
Harwani et al discover the innate immune system is abnormally sensitized to be pro-inflammatory in a rat model of hypertension.
Although inflammation has long been implicated in the development and maintenance of hypertension in humans and animals, studies have focused on the adaptive arm of the immune system. Whether the innate immune system is involved, and if so how, remain unknown. Harwani et al now show that in a rat model of hypertension, where the animals spontaneously develop hypertension as they age, the innate immune system is primed to be proinflammatory even before hypertension develops. Interestingly, although the neurohormonal modulators angiotensin II and nicotine have been reported to have opposing effects on innate immunity, both were strongly proinflammatory and exacerbated the activation of the innate immune system in the model rats. In wildtype rats, on the other hand, nicotine was anti-inflammatory, suppressing the innate response as expected. The team also found the model rats had an abundance of activated macrophages, which became yet more abundant in response to nicotine. Conversely, in the wildtype animals macrophage numbers remained low. The results suggest activation of innate immunity is a pathogenic mechanism in hypertension, and thus offer new inroads for studying, and potentially treating, the disorder.
- © 2012 American Heart Association, Inc.