Summary Exosomes , key mediators of cell-cell communication, derived from type 2 diabetes mellitus (T2DM) exhibit detrimental effects . Exercise improves endothelial function in part through the secretion of exosomes into the circulation. Extracellular superoxide dismutase (SOD3) is an important copper (Cu)-secreting antioxidant enzyme that catalyzes the dismutation of O2− to H2O2 whose activity requires the Cu transporter ATP7A. However, the role of SOD3 in exercise-induced angiogenic effects of circulating plasma exosomes on endothelial cells (ECs) in T2DM remains unknown. Here, we showed that SOD3 and ATP7A proteins were present in plasma exosomes in mice, which increased significantly after two weeks of voluntary wheel exercise. A single exercise session in humans also showed a significant increase in the expression of SOD3 and ATP7A proteins in plasma exosomes. Plasma exosomes from T2DM mice significantly reduced angiogenic responses in human EC or mouse skin wound healing models, which was associated with a decrease in the expression of ATP7A, but not SOD3, in exosomes. Exercise training in T2DM mice restored the angiogenic effects of T2DM exosomes in EC by increasing ATP7A in exosomes, which was not observed in exercised T2DM/SOD3 −/− mice. Furthermore, SOD3-overexpressing exosomes significantly improved angiogenesis in EC by increasing local H2O2 levels in a heparin-binding domain-dependent manner, as well as restoring defective wound healing and angiogenesis in T2DM or SOD3-/ mice. -. In conclusion, exercise enhances the angiogenic potential of circulating exosomes in T2DM in a SOD3-dependent manner. Exosomal SOD3 may provide an exercise mimetic therapy that supports neovascularization and wound repair in cardiometabolic diseases. |
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One way exercise may counteract the damage of diabetes is by enabling the activation of a natural system we have to grow new blood vessels when existing ones are devastated by this disease, scientists report.
Angiogenesis is the ability to form new blood vessels, and diabetes not only damages existing blood vessels, but hinders this innate ability to develop new blood vessels in the face of disease and injury, say experts at the Faculty’s Center for Vascular Biology. of Georgia Medicine.
Endothelial cells line our blood vessels and are essential for the growth of new blood vessels. Now, MCG scientists have the first evidence that in the face of diabetes, even a 45-minute session of moderate-intensity exercise allows more exosomes, submicroscopic packages packed with biologically active cargo, to deliver more of the protein, ATP7A, directly to those cells. , which can kick-start angiogenesis, they report in The FASEB Journal.
Like the more sophisticated and efficient delivery services we’ve all come to rely on, particularly during the pandemic, what exosomes carry depends on where they come from and where they’re going, says Dr. Tohru Fukai, a vascular biologist and MCG cardiologist.
While he and MCG co-author vascular biologist Dr. Masuko Ushio-Fukai aren’t yet sure where these useful exosomes come from, it’s clear that one place they reach is endothelial cells, Fukai says.
In both an animal model of type 2 diabetes and a handful of healthy 50-something people, two weeks of volunteer running on a wheel for the mice and that cardio session for the humans increased levels of ATP7A in the exosomes that They joined the endothelial cells.
At that time, the activity did not have a significant impact on the mice’s weight, the scientists note, but it did increase a marker of endothelial function and factors such as vascular endothelial growth factor, necessary for angiogenesis.
Exercise also increased the amount of the powerful natural antioxidant extracellular superoxide dismutase , or SOD3, but it is the heaviest payload of ATP7A, which is also known to deliver the essential mineral copper to cells, which is key to making good use of it. of the SOD3 present, says Ushio-Fukai.
SOD3, is an important natural antioxidant produced by vascular smooth muscle cells in the walls of blood vessels, as well as skeletal muscle cells, which helps us maintain healthy levels of reactive oxygen species, or ROS. ROS is a natural byproduct of our use of oxygen that is an important cellular signal, enabling a variety of functions. But in diabetes, high blood sugar levels result in high levels of ROS which, in turn, hinder important normal functions.
The Fukais have shown that ATP7A levels are reduced in diabetes.
They now also have some of the first evidence that exosomes circulating in the plasma of sedentary animal models of type 2 diabetes actually alter angiogenesis when plated with human endothelial cells, as well as in an animal model of wound healing. wounds.
Scientists suggest that synthetic exosomes, already being studied as drug delivery mechanisms, could one day function as an "exercise mimetic" to improve patients’ ability to grow new blood vessels when diabetes has impaired their ability. innate
In fact, they already generated exosomes in which SOD3 is overexpressed and found improved angiogenesis and healing in a mouse model of diabetes.
The way it’s supposed to work is that SOD3 is naturally silenced in endothelial cells, so they have to get it from other cells, Ushio-Fukai notes, hence the importance of exosome delivery. SOD3 must then bind to endothelial cells at its natural site called the heparin-binding domain, and the copper transporter ATP7A must be present to allow SOD3 to be active there, Fukai says. Both ATP7A and the binding site are key, Fukai notes. For example, when they removed the attachment site for endothelial cells, which can happen in nature, the benefits were lost.
Once on the scene and active, SOD3 converts superoxide ROS into hydrogen peroxide, or H2O2, another signaling ROS that helps maintain normal endothelial cell function. The Fukais have reported that in human endothelial cells, overexpression of SOD3 promotes angiogenesis by increasing H2O2.
A copper connection also runs throughout this process, as endothelial cells regularly use a lot of copper, and ATP7A, known to transport the essential mineral we consume in foods like nuts and whole grains, depends on copper itself. .
Physical exercise, such as running or walking on a treadmill, causes muscles to contract, which in turn causes the release of exosomes into the blood.
When Fukai was a postdoc in the Section of Cardiology at Emory University, he was part of the research group that was the first to show that exercise increases SOD3 activity. SOD3 levels decrease with age and with some disease states such as diabetes and hypertension.
Exosomes are being studied as biomarkers for a wide range of diseases such as cancer and diabetes, as well as precise tools for delivering treatments. For example, exosomes produced by a cancer cell will grow back into a cancer cell.
About 1 in 10 Americans has diabetes, according to the Centers for Disease Control and Prevention.
