Against all odds Dr. Kassiri identifies ADAM17 as an important regulator of atherosclerosis
Co-First Authors, Dr. Ilamaran Meganathan (left), and Tolga Kilic
Cholesterol is one of the main villains in atherosclerosis, the leading cause of cardiovascular disease. Atherosclerosis is a condition where fat deposition inside the blood vessel forms a plaque that grows and eventually clog the vessels disrupting blood flow. When this happens, the amount of oxygen and nutrients delivered to your heart and rest of the body is low. At that point, a heart attack is imminent.
Although one could argue that we are what we eat, inside your body the cells have no choice and they have to deal with the food that you give them. Smooth muscle cells are part of the blood vessel’s wall. These cells help in contracting the blood vessels and in maintaining blood flow. When cholesterol in the blood is high, smooth muscle cells start to act like macrophages, and end up “eating” more fat than they can manage and start to form bubbles. Not surprisingly these are called foam cells. When they reach this stage, they also change their appearance and function and become macrophage-like. This is not great because macrophages are the main cells involved in inflammation. They too can get foamy like smooth muscle cells but their impact is far greater, leading to an inflamed state. When this happens, cells tend to die off more quickly and lead to protective measures including the formation of an atherosclerotic plaque. Once this has occurred, a vicious cycle begins in which more fat leads to more foam and this leads to larger plaques.
On the surface of smooth muscle cells there are proteins that help them to communicate with other cells depending on the environment around them. The ADAM protein family (short form for - a disintegrin and metalloproteinase) are a group of enzymes that mediate cell function and cell-cell communication. For example, a smooth cell communicates with macrophages using proteins as messengers. When the environment around them changes, such as when there is too much fat in the blood, more of these proteins might appear on the cell surface. That is exactly what happens with one protein named ADAM17 during atherosclerosis. The increased amount of ADAM17 might then change the message passing from one cell to another.
That leads to a very important question. If atherosclerosis involves increased levels of ADAM17, what would happen with less protein? Would it prevent the disease progression?
That’s where Dr. Kassiri’s lab, led by post-doctoral fellow Ilamaran Meganathan, and MSc student Tolga Kilic, comes into the picture. They wanted to know whether they could protect against the formation of atherosclerotic plaques by reducing the amount of ADAM17 in smooth muscle cells. Their findings are now published in the December issue of the journal, Atherosclerosis.
The team generated a mouse model lacking ADAM17 in their smooth muscle cells and induced atherosclerosis in these animals by feeding them a high cholesterol diet. Surprisingly, the smooth muscle cells lacking ADAM17 turned into foam cells faster, trapping more fat inside them. The communication between smooth muscle cells with macrophages around them also changed. The macrophages became more stressed (favoring inflammation) and released harmful chemicals worsening inflammation which caused the plaque formation to be faster.
Ah, and if you are wondering if females are protected from these changes they are not! All the findings were similar in females, so ADAM17 participates in regulating atherosclerosis progression in both biological sexes.
Their study unveils a surprising twist in our understanding of cardiovascular disease. While ADAM17 was initially thought to be a culprit in atherosclerosis, Dr. Kassiri’s work shifts the paradox proving that ADAM17 is actually a protector against atherosclerosis development.
This is a reminder of the complex role of proteins in disease progression and the need to continue research into all mechanistic insights. This is especially important when developing new drugs as something that may have been shrugged off as a contributor of disease - like ADAM17 - might actually be a signal of the body’s own way to cope and could lead us down a path to treatment and improved health.