Researchers at the Cleveland Clinic have uncovered a crucial link between the gut microbiome and cardiovascular disease, potentially paving the way for new heart failure treatments. A study published in Nature Communications highlights how a substance called phenylacetylglutamine (PAG), produced by gut bacteria, interacts with heart cells in ways that may contribute to heart failure.
The study found that PAG, once produced by gut bacteria, is absorbed and processed in the liver before entering the bloodstream. Once in circulation, PAG interacts with beta-2 adrenergic receptors on heart cells. This interaction affects how strongly the heart muscle contracts, which researchers believe plays a role in the development of heart failure. By mutating certain parts of the beta-2 adrenergic receptor that were previously thought to be unrelated to signaling, researchers were able to prevent PAG from negatively affecting the receptor’s function in preclinical models.
This discovery is the latest in a series of studies led by Dr. Stanley Hazen, chair of Cardiovascular and Metabolic Sciences at Cleveland Clinic’s Lerner Research Institute. Dr. Hazen’s previous research showed that higher levels of circulating PAG are linked to an increased risk of heart failure and worse outcomes in those who already have the condition. The findings from this study bring researchers closer to developing treatments that could target this pathway, offering hope for better heart failure prevention.
Challenges with Current Heart Failure Treatments
Beta-blockers, a common treatment for heart failure and high blood pressure, work by targeting beta adrenergic receptors, which play a crucial role in the body’s fight-or-flight response. This response, while essential for survival, can cause long-term damage to the heart if triggered too frequently, contributing to heart failure. Beta-blockers function by blocking hormones like adrenaline from binding to these receptors, thereby slowing the heart rate, reducing strain on the heart, and opening blood vessels.
Previous research by Dr. Hazen’s team showed that high levels of PAG in the bloodstream are associated with the presence and severity of heart failure. They found that PAG exacerbates heart failure-related symptoms, such as a weakened heartbeat. However, these effects were reversed in preclinical models when treated with common beta-blockers, reinforcing the connection between PAG, heart failure, and beta-adrenergic receptors.
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New Insights Into PAG And Potential Treatment Approaches
In their latest study, Dr. Hazen’s team explored how PAG interacts with beta-adrenergic receptors. The research, led by Prasenjit Saha, PhD, involved mutating different areas of the beta-2 adrenergic receptor to test its interaction with epinephrine, the natural hormone also known as adrenaline. They found that mutating certain sites allowed the adrenaline binding site to remain intact and functional, but the receptor was no longer negatively affected by PAG.
Dr. Hazen explained that these findings suggest beta-2 adrenergic receptors can be regulated through a second PAG binding site. This site acts as a “dimmer switch” for the adrenaline signaling pathway, allowing for more precise regulation. Since PAG interacts with the receptor at a different location than adrenaline, it may be possible to block the harmful effects of PAG without interfering with the body’s natural adrenaline signals.
These insights could lead to the development of new drugs that offer a more refined way to regulate beta-2 adrenergic receptors, going beyond the capabilities of current treatments. Dr. Hazen and his team are now working to create medications that target the PAG pathway and its interactions with adrenergic receptors, offering a novel approach to treating cardiovascular disease.
This research was supported by grants from the National Heart, Lung, and Blood Institute. Dr. Hazen, who holds patents related to cardiovascular diagnostics and therapeutics, also reports consulting for P&G and receiving research funds from the company for unrelated work.