Shortly after cholesterol and fat begin to deposit on the lining of the blood vessels that supply the heart, the smooth muscle cells that give strength and flexibility to the blood vessels begin to enlarge and multiply.
ATIC-associated de novo purine synthesis is critically involved in proliferative arterial disease Summary Background: Vascular smooth muscle cell (VSMC) proliferation is a hallmark of arterial diseases, especially in arterial restenosis after angioplasty or stent placement. VSMCs reprogram their metabolism to meet the increased lipid, protein, and nucleotide requirements for their proliferation. De novo purine synthesis is one of the critical pathways for nucleotide synthesis. However, its role in VSMC proliferation in these arterial diseases has not been defined. Methods: De novo purine synthesis in proliferating vascular smooth muscle cells (VSMCs) was assessed by liquid chromatography-tandem mass spectrometry. The expression of ATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase), the critical bifunctional enzyme in the last two steps of the de novo purine synthesis pathway, was evaluated in proliferative arterial neointimal VSMCs. Global and specific knockouts of VSMCs from Atic mice were generated and used to examine the role of ATIC-associated purine metabolism in arterial neointima formation and atherosclerotic lesions. Results: In this study, we found that de novo purine synthesis was increased in proliferative VSMCs. Upregulated purine synthesis genes, including the bifunctional enzyme critical in the last two steps of the de novo purine synthesis pathway ATIC , were observed in the neointima of injured vessels and atherosclerotic lesions in both mice and humans. Global or specific deletion of Atic in VSMCs inhibited cell proliferation, attenuating arterial neointima in mouse models of atherosclerosis and arterial restenosis. Conclusions: These results reveal that de novo purine synthesis plays an important role in VSMC proliferation in arterial disease. These findings suggest that targeting ATIC is a promising therapeutic approach to combat arterial diseases. |
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While scientists studying the phenomenon suspect that these vascular smooth muscle cells are trying to help, this atypical behavior of these strong cells contributes to coronary artery disease, the most common type of heart disease in the United States.
In a small vicious circle, stents and bypass grafts used to treat coronary artery disease can provoke the same response. Now, scientists at the Medical College of Georgia report how cells enable this unhealthy growth and a new target to intervene.
The endothelial cells that line our blood vessels are in constant communication with the layers of vascular smooth muscle cells that line them and play a key role in regulating our blood pressure, says Yuqing Huo, MD, PhD, and director of the Vascular Inflammation Program. at the MCG Vascular Biology Center.
In states of good health, for example, the two cell types share messages about how it’s time for our blood vessels to dilate a little because we’re exercising. Early in vascular disease, however, conversations change, says Huo, corresponding author of the study in the American Heart Association journal Circulation .
"They get the message that something is wrong ," Huo says, and the existing cells become exponentially larger and begin to proliferate , which these cells normally don’t do, perhaps in an effort to make more room inside for the flow of energy. blood, since cholesterol and fat are narrowing the existing passage.
“Normally, smooth muscle cells provide strength… if they start to proliferate a lot, their identity changes,” Huo says.
Whatever the reason, the result is further narrowing and scarring of the vital blood passage and worsening of the disease. The scientists then looked at the building blocks needed to enable the unhealthy response.
They knew that growing more and more cells requires more DNA, RNA, and the proteins they produce. For that to happen, more purines are required, one of two chemicals in the body that are used to make the building blocks of DNA, in this case adenine and guanine.
What they didn’t know was precisely how these cells produce more purine when faced with arterial disease, says Dr. Qian Ma, Huo’s postdoctoral fellow and first author of the study. There are two fundamental ways that cells produce purine: one is to essentially make it from scratch, called de novo purine synthesis , and the other is to recycle .
MCG scientists are the first to discover that de novo purine synthesis, which is more energy-intensive, increases in this scenario, says Ma. In scar tissue and plaque within the blood vessels of mice and humans, Huo, Ma and colleagues also found increased expression of ATIC, a gene essential for purine production.
When they removed ATIC throughout the body, as well as specifically in vascular smooth muscle cells, they inhibited purine production, which decreased DNA and RNA production, and subsequent proliferation of smooth muscle cells.
The net effect of less ATIC was the reduction of scar tissue formation in animal models of atherosclerosis and restenosis, or the narrowing of blood vessels, including buildup within the stents themselves, which can occur after procedures such as angioplasty to opening clogged vessels and placing stents to help keep them open. “It takes away one of the building blocks of DNA,” says Ma. “The blood vessels remained normal. The lumen remained open.”
The answer shows that purine production plays a key role in the proliferation of smooth muscle cells and points to ATIC as a logical point to intervene, the scientists say. “Our model shows that this ATIC is important and targetable,” says Ma.
While there is still much work to be done, Huo suspects that an ATIC inhibitor would work best early in the disease process when an abnormal stress test indicates that cholesterol and fat in the blood are beginning to deposit inside the blood vessels. and that applying an inhibitor to stents placed inside diseased blood vessels would be a good way to deliver it.
Scientists hope their findings will inspire drug developers to create a specific inhibitor for this signature contributor to heart disease, which is the leading cause of death for men and women in the United States, according to the Centers for Disease Control and Prevention. Disease Prevention.
“Our role is just to provide a target and other people will generate a drug ,” Ma says of a potential therapy that would likely be used alongside other approaches such as statins, which lower cholesterol.
Huo’s lab also plans to examine when vascular disease is not present, whether smooth muscle cells choose to use purine recycling to meet the much lower demand for protein instead of the multi-step production process, which includes ATIC.
The scientists note that making purine from scratch is often the method used to rapidly divide cancer cells, and that ATIC expression is also high in some of these cells, which appears to make ATIC a logical treatment target for people as well. cancer. In fact, one way the old chemotherapy drug methotrexate is thought to work is by inhibiting ATIC, although the drug has multiple targets and potentially serious side effects, including sudden vision loss and seizures.
“Both tumors and smooth muscle cells under stress need to proliferate a lot and if we block this pathway, we will reduce their proliferation,” says Ma.
Newer, more specific ATIC inhibitors are in various stages of study against cancer, but scientists noted that when they tested a couple of these newer inhibitors, even at high doses, they apparently are not potent or specific enough to make the type of positive changes in the vascular smooth muscle cells they obtained with their genetic manipulations.
The inhibitors likely cannot be used long-term in either scenario, as they could interfere with the functioning of cells that need to proliferate, such as skin cells and cells lining the gastrointestinal tract, Huo adds. But treatment at strategic points and for limited periods of time should not harm even normally proliferating cells.
The scientific team is also studying the pathways for purine production in pulmonary hypertension, which is destructive high blood pressure in the lungs and the right side of the heart.
Studies have indicated that high levels of ATIC correlate with poor survival in liver cancer and that reducing ATIC expression reduces cancer cell proliferation and migration.
Coronary stents have been in use in this country since 1994, and drug-eluting stents, coated with drugs that reduce clot formation, came into use five years later. Stents are a primary intervention for patients with a pair of diseased coronary arteries and can become blocked through some of the same processes that led to the need for stents, as well as trauma caused to the lining of the blood vessel by their placement.
