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Circulation ( IF 35.5 ) Pub Date : 2019-12-09 , DOI: 10.1161/circulationaha.119.044630
Tracy Hampton

Lamin A/C (LMNA) is one of the most frequently mutated genes associated with dilated cardiomyopathy, which arises when the left ventricle is enlarged, dilated, and weak. Sudden cardiac death may be the first manifestation of LMNA-related dilated cardiomyopathy, because of abnormal heart rhythms.


New research reveals a possible drug target for dilated cardiomyopathy.


To uncover the mechanisms that link mutations in LMNA to cardiac arrhythmias, a team led by investigators at the Stanford University School of Medicine conducted experiments with patient-specific induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). In the study, which is published in Nature, cells with a lamin mutation failed to beat properly, as seen in patients with the disease.


Cells with a mutation in lamin, which forms part of the nuclear envelope, also had fewer regions of tightly packed DNA, or heterochromatin, which could affect gene expression. Additional experiments revealed that nearly 250 genes were more highly expressed in mutated cells than in normal cells. Many of the genes were part of the platelet-derived growth factor, or PDGF, signaling pathway. This pathway is important in the formation of blood vessels and normally is active only during development or stress.


Inhibiting the PDGF signaling pathway restored regular, rhythmic beating in the mutant iPSC-CMs in vitro. The findings suggest that several inhibitors of the PDGF pathway that are currently approved as therapies for patients with cancer, such as sunitinib, sorafinib, and axitinib, may be repurposed for treating LMNA-related dilated cardiomyopathy. Additional studies are needed, however, because these drugs may be associated with cardiac toxicity.


“By combining several new technologies, including creation of patient-specific heart cells, our study provides an unprecedented understanding of the relationship between LMNA gene errors and development of heart disease,” said senior author Dr Joseph Wu. “These findings pave the way for disease-specific therapeutics—or precision medicine—in the future.”


Lee J et al. Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy. Nature. 2019;572:335–340. doi: 10.1038/s41586-019-1406-x


A newly discovered sex-specific molecular pathway promotes metabolic flexibility in female mice and allows their skeletal muscle to adapt to fasting conditions.


Skeletal muscle regulates fat storage, glucose uptake, and other processes involved in metabolism, and during times of low nutrient availability or exercise, skeletal muscle switches from using glucose to oxidizing fatty acids as a source of fuel.


“Defective handling of fuels like glucose and fatty acids is found in diseases including obesity and diabetes, and even in aging. Surprisingly, the regulatory mechanisms involved are still not clear,” said Dr Chi Bun Chan, of The University of Hong Kong.


In their Science Signalingstudy designed to understand the pathways involved in switching metabolic fuel sources, Dr Chan and his colleagues found that fasting in female mice led to production of brain-derived neurotrophic factor (BDNF) in the gastrocnemius muscle of the calf. This in turn led to increased activity of AMP-activated protein kinase and enzymes involved in fatty acid oxidation, causing the gastrocnemius in fasted female mice to switch from using glucose to fatty acids.


When the investigators bred mice lacking BDNF exclusively in skeletal muscle, they observed that female rodents could not switch fuel sources during fasting, leading to weaker muscles and insulin resistance. These effects were not seen in male BDNF-deficient mice.


Although BDNF, which is best known for promoting the development and survival of neurons, may not have the same effects in human muscle, the findings suggest that the factor may help regulate metabolism in addition to its role in the nervous system.


“Reinforcing BDNF signaling in muscle may be beneficial to pathological conditions with poor metabolic regulation, like obesity and diabetes,” said Dr Chan. The team’s previous work revealed that adding orally active BDNF mimetics to the drinking water of obese mice reduced their body weight and lipid levels, and improved their insulin sensitivity.


Yang X et al. Muscle-generated BDNF is a sexually dimorphic myokine that controls metabolic flexibility. Sci Signal. 2019;12:eaau1468. doi: 10.1126/scisignal.aau1468


Immune cells engineered to recognize and destroy malignant cells have been used successfully to treat cancer, and now investigators have used a similar approach against cardiac fibrosis. Cardiac fibrosis is seen in most forms of heart disease, but few treatments improve symptoms and no therapies directly target the processes involved.


In cancer therapy, cytotoxic T cells are redirected to recognize specific antigens on cancer cells using either a modified T-cell receptor or a chimeric antigen receptor (CAR). With this strategy in mind, researchers from the University of Pennsylvania identified a candidate target protein on activated cardiac fibroblasts from diseased human hearts. As described in a Naturestudy, modified T cells designed to recognize this protein, called fibroblast activation protein, reduced cardiac fibrosis and improved heart function when administered to mice with heart injury and developing fibrosis.


CAR T immunotherapy has been approved by the US Food and Drug Administration for some forms of cancer, but more work is needed to assess the safety of its use in human heart disease and to determine whether fibroblast activation protein is the best target. The results of this study, however, provide proof-of-concept for the possibility of targeting cardiac fibrosis with engineered T cells and immunotherapy.


“While much more research is needed before we can introduce this approach into the clinical setting, this marks a significant step forward in our efforts to treat—and potentially reverse—a condition that accelerates the progression of heart failure,” said senior author Dr Jonathan Epstein.


Aghajanian H et al. Targeting cardiac fibrosis with engineered T cells. Nature. 2019;573:430–433. doi: 10.1038/s41586-019-1546-z

更新日期:2019-12-11
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