The results published in the journal Communication Nature point to the copper transporter ATP7A as a potential new therapeutic target in the treatment of cardiovascular diseases such as heart attacks, peripheral artery disease and stroke.
“Our article talks about a newly discovered function of ATP7A,” says Dr. Masuko Ushio-Fukai, vascular biologist at MCG’s Center for Vascular Biology. “Our paper shows that ATP7A binds directly to the vascular endothelial growth factor receptor, called VEGFR2, to stabilize it, to regulate the receptor itself,” she says of the receptor that allows us to produce new blood vessels from our existing vessels in a process called angiogenesis.
They have already shown that in diseases like diabetes, a major risk factor for cardiovascular disease, ATP7A expression is down, VEGFR2 degradation is up, and a healthy copper balance is lost, which contributes to many of the problems that these patients face like heart attacks and impaired wound healing, says Dr. Tohru Fukai, vascular biologist and cardiologist at VBC.
It was these findings that led the co-corresponding authors of the new article to believe that there could be a direct link between ATP7A and the VEGF receptor.
Endothelial cells line our blood vessels and VEGF stimulates the proliferation and movement of these cells, which form the basis and stimulation of new repairing blood vessels. VEGF receptors on endothelial cells are a starting point for angiogenesis, explains Fukai.
In healthy humans, angiogenesis occurs to some extent throughout life, but in conditions like diabetes, when this ability is probably most needed, it is impaired, scientists say.
They suspect and continue that the essential crosstalk they have now discovered between transporter and receptor also occurs during aging when, like many bodily functions and factors, ATP7A levels naturally begin to decline.
The next steps in their work include identifying drugs that would increase and stabilize ATP7A levels and, therefore, the VEGF receptor, Ushio-Fukai explains.
Reddish metallic copper, an essential micronutrient, has long been known to stimulate endothelial cell proliferation and migration – copper causes new blood vessels to grow, and removal of copper reduces tumor growth in animal models – and copper concentrations are increased in tissue formation. new blood vessels, say scientists. But how copper stimulates the formation of new blood vessels is unknown, they say.
ATP7A typically resides in the cell’s trans-Golgi network – a sort of bus station inside the cell that sends new proteins to where it’s needed – where it supplies copper to enzymes that need them. the micronutrient is activated and functional. These enzymes include superoxide dismutase, which breaks down harmful byproducts of oxygen utilization like reactive oxygen species, which play a key role in various conditions like cardiovascular disease and diabetes, as well as lysyl oxidase, which is essential for the production of connective tissue in the body and essential for healthy bones, hair and more, says Fukai.
When too much copper builds up inside cells, as they have seen in conditions like diabetes, ATP7A also has the job of removing the excess, as too much or too little can be destructive. “Copper is both very toxic and essential,” notes Fukai.
Now MCG scientists have shown that VEGF pushes ATP7A out of the trans-Golgi network to the cell membrane where it binds and stabilizes the VEGF receptor. They also showed that the loss of ATP7A in endothelial cells promotes the formation of autophagosomes, which essentially form a membrane net around everything about to be consumed, and which now target VEGFR2 for degradation. The excess copper that begins to build up inside the cell can further hamper useful angiogenesis.
Essential copper enzymes cannot be activated and excessive amounts of copper cannot be exported either. ATP7A would be one of the therapeutic targets to help correct this. “
Dr Masuko Ushio-Fukai, Vascular Biologist, MCG Vascular Biology Center
The collective results mean that the copper transporter ATP7A is needed for the formation of new blood vessels and the restoration of blood flow in ischemic cardiovascular disease, they write.
The fact that copper is essential for angiogenesis was demonstrated decades ago, when it was discovered that simply applying copper to endothelial cells stimulates angiogenesis, Ushio-Fukai explains.
There has been some indication that copper’s role in angiogenesis has worked through the delivery of copper by ATP7A to copper-containing enzymes like superoxide dismutase. “Our article changes that concept,” she says.
The conditions that can trigger the exit of ATP7A from the trans-Golgi network are signals such as that a large amount of copper is present in the cytoplasm, a fluid-filled pocket in the cell that contains most of its contents, including including the trans-Golgi network; a lack of oxygen, called hypoxia, being supplied to tissue, such as occurs in heart disease and peripheral arteries; and insulin.
Too much copper inside cells is definitely bad, where it can function like what Fukai calls an “atomic weapon” to vigorously produce destructive free radicals. Without enough work by ATP7A to keep copper levels balanced, levels of the metal continue to rise while essential activities of copper-containing enzymes decline.
Although our cells naturally make copper receptors, we need to consume the essential micronutrient itself. Foods rich in copper include oysters and other shellfish like lobster and baby clams, shiitake mushrooms, tofu and soybeans, sweet potatoes, sesame seeds and nuts like cashews and walnuts as well as leafy greens like spinach and kale.
Georgia Medical College at Augusta University