Researchers have uncovered crucial information about the relationship between the gut microbiome and cells in the context of cardiovascular disease. According to a study published in Nature Communications, gut bacteria produce a substance called phenylacetylglutamine (PAG) as a waste product. After being absorbed and processed in the liver, PAG enters the bloodstream and interacts with newly identified sites on beta-2 adrenergic receptors found on heart cells.
Cleveland Clinic researchers have uncovered crucial information about the relationship between the gut microbiome and cells in the context of cardiovascular disease. According to a study published in Nature Communications, gut bacteria produce a substance named phenylacetylglutamine (PAG) as a waste product. After being absorbed and processed in the liver, PAG enters the bloodstream and interacts with newly identified sites on beta-2 adrenergic receptors found on heart cells.
PAG was shown to interact with beta-2 adrenergic receptors, affecting how strongly heart muscle cells contract, which researchers believe may lead to heart failure. They demonstrated that altering specific parts of the beta-2 adrenergic receptor that were previously considered unrelated to signaling in preclinical models prevented PAG from diminishing the receptor’s function.
This research is part of a broader investigation into PAG led by Stanley Hazen, MD, PhD, who chairs Cardiovascular and Metabolic Sciences at Cleveland Clinic’s Lerner Research Institute and co-leads the Preventive Cardiology section. Dr. Hazen’s previous work indicated that higher levels of circulating PAG correlate with an increased risk of developing heart failure and contribute to poorer outcomes for those already affected by it. His lab also established that the gut-derived PAG signaling pathway is linked to various features related to heart failure and cardiovascular disease risk. These new findings bring us a step closer to potentially targeting this pathway for improved heart failure prevention treatments, according to Dr. Hazen.
Limitations of Blocking Beta-2 Adrenergic Receptors
A standard medication for managing heart failure and blood pressure, known as beta-blockers, targets the body’s “fight-or-flight” response, which is regulated by beta adrenergic receptors and is essential for survival. However, repeated activation of this response may result in cumulative heart damage, fostering the development of heart failure. Sathyamangla Prasad, PhD, who co-authored the study, contributed his knowledge on beta-adrenergic receptors and heart failure.
Beta-blockers function as on/off switches for beta-2 adrenergic receptors, managing stress on the heart. They work by preventing hormones like adrenaline from fitting into their designated spots on beta-2 adrenergic receptors, much like a key entering a lock.
Beta-blockers occupy the same binding sites intended for adrenaline, hindering its action and leading to a reduction in heart rate, decreased heart strain, and dilated blood vessels. Prior research by this team linked elevated PAG levels to the presence and severity of heart failure, highlighting how PAG contributes directly to heart failure symptoms, such as weakened heartbeats. The negative impact of PAG on heart failure indicators was reversed with a common beta-blocker in preclinical experiments, solidifying the connection between PAG, heart failure, and beta-adrenergic receptors.
New PAG Discoveries Present Additional Treatment Options
The current studies explored the intricate interactions between PAG and beta-adrenergic receptors. Prasenjit Saha, PhD, the primary author and a member of Dr. Hazen’s team, conducted mutations on various sections of the beta-2 adrenergic receptor to see if signaling could still occur with the natural hormone epinephrine (adrenaline). Preclinical trials demonstrated that by altering certain areas, the adrenaline binding site remained intact and operational, yet the mutated receptor was no longer negatively influenced by PAG.
Dr. Hazen interprets these outcomes as evidence that beta-2 adrenergic receptors can be modulated through an alternative PAG binding site that serves as a “dimmer switch” for the adrenaline signaling pathway. Since PAG interacts with the receptor at a different site compared to adrenaline, Dr. Hazen speculates that targeted intervention could block harmful PAG signaling from gut microbes while still permitting the body’s natural adrenaline signals to function effectively.
Dr. Hazen and his team believe their findings hint at a novel approach to developing drugs that modulate beta-2 adrenergic receptors, offering a finer regulatory strategy than current options available. They are actively pursuing the creation of medications that focus on the PAG pathway and its relationship with adrenergic receptors for treating cardiovascular diseases.
“An advanced beta-blocker that selectively inhibits harmful adrenergic receptor signaling while permitting beneficial signals could revolutionize treatments for cardiovascular disease,” asserts Dr. Hazen. “Such innovations have the potential to enhance the quality of life for patients dependent on beta-blockers to manage their stress responses.”
This research received funding from the National Heart, Lung, and Blood Institute.
