Existing cancer drugs could be repurposed as treatments for vascular inflammation, according to new research from the University of California San Diego School of Medicine.
Publishing their findings in Cell Reports, the authors describe new insights into the way G-protein-coupled receptors (GPCRs) work within cells to influence inflammation using cellular “waste disposal systems.”
Vascular inflammation (inflammation of the blood vessels) is a significant contributing factor in the early phases of atherosclerosis, a disease whereby plaque builds up inside the arteries and which
Cardiovascular disease is the leading cause of death worldwide, so identifying any potential targets for therapies addressing cardiovascular disease or its causes — such as vascular inflammation — is a priority.
GPCRs are embedded in the membranes of all cells, where they mediate cells’ responses to their external environments. GPCRs change shape when a nutrient or other molecule binds to them.
Part of this shape change involves a G-protein inside the cell docking to the GPCR on the internal side of the membrane, which initiates a series of molecular changes.
Scientists know that GPCRs are important in maintaining many biological functions such as smell, sight, taste, allergic responses, blood pressure, and heart rate.
They also know that when GPCRs malfunction, they can contribute to a range of diseases. However, many of the basic functions of GPCRs are still not fully understood.
The research team from this latest study investigated how a process called ubiquitination affects GPCR functions in the cells that line blood vessels.
Ubiquitination is when proteins are tagged by enzymes with molecules called ubiquitin, acting as a kind of flag to let the cell know that this protein can be disposed of.
However, the team discovered that in these cells, the GPCR activates the E3 ligase enzyme that initiates ubiquitination, which in turn activates an inflammation-promoting protein called p38. This is a markedly different mechanism to the usual process of ubiquitination.
“We were surprised to discover that GPCRs and inflammation are influenced by ubiquitination — a process that was previously thought to only mark proteins for destruction,” explains senior author JoAnn Trejo. “Instead, we’ve unveiled new insights into both GPCR function and ubiquitination.”
According to Trejo, this is the first time that E3 ligases have been identified as playing a role in vascular inflammation, making it a viable target in developing treatments for this condition.
The good news is that several drugs that are currently used as cancer treatments have already been approved by the Food and Drug Administration (FDA); such drugs inhibit these E3 ubiquitin ligases, and researchers are currently studying more in clinical trials. So, it may be possible to also use these drugs to treat vascular inflammation.
However, Trejo warns that “the field is really in its infancy,” and that “the number of E3-targeting drugs approved or in clinical trials is remarkably small.” This is further complicated by the sheer number of different E3 ligases in the body, thought to be between 600 and 700, and which are associated with a variety of biological functions.
Although vascular inflammation is a known contributor to atherosclerosis, Medical News Today recently reported on a study that found inflammation may actually help keep heart attack and stroke at bay in more advanced cases of the condition.