Working mannequin illustrating how cleaved N-terminal gasdermin D could create a pro-arrhythmic substrate for atrial fibrillation growth. The determine was created with BioRender.com. Credit score: European Coronary heart Journal (2025). DOI: 10.1093/eurheartj/ehaf024
Atrial fibrillation (AF) is a standard type of coronary heart arrhythmia, a severe situation through which the center beats so quick that its higher chambers, the atria, quiver. This irregular heartbeat can enhance the danger of extreme situations, together with coronary heart failure, dementia and stroke.
“My lab has been studying the role of inflammation in the initiation and persistence of AF for many years. In this multidisciplinary study, we investigated the function of gasdermin D, a key participant in inflammatory pathways, in atrial heart cells and its potential contribution to AF,” stated corresponding creator Dr. Na Li, professor of drugs at Baylor Faculty of Medication.
The work is revealed within the European Coronary heart Journal.
Earlier research have proven that in immune cells, gasdermin D is minimize into two fragments; NT-gasdermin D, which might set off cell demise in immune cells, and CT-gasdermin D, whose perform is unknown. “Although prior studies suggest that gasdermin D activation could contribute to a heart attack by causing cell death, the precise function of gasdermin D in heart cells remains poorly understood,” Li stated.
The researchers studied sections of human atria to evaluate the degrees of gasdermin D and located elevated ranges of the protein in AF sufferers. The group additionally labored with a mouse mannequin through which they elevated the degrees of NT-gasdermin D solely in atrial coronary heart cells. “These mice had an increased susceptibility to AF,” Li stated.
Atrial cardiomyocyte-specific overexpression of N-terminal gasdermin D enhances atrial fibrillation susceptibility. Credit score: European Coronary heart Journal (2025). DOI: 10.1093/eurheartj/ehaf024
Additional research confirmed that NT-gasdermin D doesn’t kill a lot of the coronary heart cells however mediates the formation of pores within the cell membrane. The pores facilitate the discharge of coronary heart cell-produced cytokines, immune mediators that promote the infiltration of immune cells to the atria, which might provoke occasions resulting in atrial dysfunction. Apparently, on the similar time the cells enhanced membrane-repair mechanisms, which acted as a countermeasure to pore formation and prevented atrial cell demise.
“Additionally, NT-gasdermin D directly targeted mitochondria, the cell’s main source of energy, mediating pore formation and increasing the release of mitochondrial reactive oxygen species (ROS),” stated first creator Dr. Yue Yuan, a postdoctoral affiliate within the Li lab. “As ROS pours into the cells through the mitochondria, it triggers the abnormal release of calcium, which in turn promotes events that generate arrhythmias.”
Supporting these findings, the group discovered that mitochondria-specific antioxidant MitoTEMPO, which scavenges ROS, mitigated arrhythmias induced by NT-gasdermin D. A mutant NT-gasdermin D missing the power to type pores did not trigger mitochondrial dysfunction or induce atrial arrhythmia. And eliminating the gene for gasdermin D additionally prevented spontaneous AF growth within the animal mannequin.
“Our study reveals that NT-gasdermin D plays a novel role in AF development through multifaceted mechanisms,” Yuan stated. “Our findings support that atrial NT-gasdermin D contributes to heart arrhythmias via a unique mechanism that does not involve cell death but promotes mitochondrial dysfunction.”
“The findings suggest that mitochondrial-targeted therapy, either by reducing ROS production or inhibiting gasdermin D, may prevent triggering AF,” Li stated. “This positions gasdermin D as a promising target for novel therapeutic option for AF.”
Different contributors to this work embody Pascal Martsch, Xiaohui Chen, Enrique Martinez, Luge Li, Jia Track, Theresa Poppenborg, Florian Bruns, Jong Hwan Kim, Markus Kamler, James F. Martin, Issam Abu-Taha and Dobromir Dobrev. The authors are affiliated with a number of of the next establishments: Baylor Faculty of Medication, College Duisburg-Essen, the Texas Coronary heart Institute and the College of Montreal.
Extra info:
Yue Yuan et al, Atrial cardiomyocyte-restricted cleavage of gasdermin D promotes atrial arrhythmogenesis, European Coronary heart Journal (2025). DOI: 10.1093/eurheartj/ehaf024
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