(Press-News.org) Atrial fibrillation (AF) is a common form of heart arrhythmia, a serious condition in which the heart beats so fast that its upper chambers, the atria, quiver. This irregular heartbeat can increase the risk of severe conditions, including 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,” said corresponding author Dr. Na Li, professor of medicine at Baylor College of Medicine.
The work is published in the European Heart Journal.
Previous studies have shown that in immune cells, gasdermin D is cut into two fragments; NT-gasdermin D, which can trigger cell death in immune cells, and CT-gasdermin D, whose function 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 said.
The researchers studied sections of human atria to assess the levels of gasdermin D and found increased levels of the protein in AF patients. The team also worked with a mouse model in which they increased the levels of NT-gasdermin D only in atrial heart cells. “These mice had an increased susceptibility to AF,” Li said.
Further studies showed that NT-gasdermin D does not kill most of the heart cells but mediates the formation of pores in the cell membrane. The pores facilitate the release of heart cell-produced cytokines, immune mediators that promote the infiltration of immune cells to the atria, which can initiate events leading to atrial dysfunction. Interestingly, at the same time the cells enhanced membrane-repair mechanisms, which acted as a countermeasure to pore formation and prevented atrial cell death.
“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),” said first author Dr. Yue Yuan, a postdoctoral associate in 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 team found that mitochondria-specific antioxidant MitoTEMPO, which scavenges ROS, mitigated arrhythmias induced by NT-gasdermin D. A mutant NT-gasdermin D lacking the ability to form pores failed to cause mitochondrial dysfunction or induce atrial arrhythmia. And eliminating the gene for gasdermin D also prevented spontaneous AF development in the animal model.
“Our study reveals that NT-gasdermin D plays a novel role in AF development through multifaceted mechanisms,” Yuan said. “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 said. “This positions gasdermin D as a promising target for novel therapeutic option for AF.”
Other contributors to this work include Pascal Martsch, Xiaohui Chen, Enrique Martinez, Luge Li, Jia Song, Theresa Poppenborg, Florian Bruns, Jong Hwan Kim, Markus Kamler, James F. Martin, Issam Abu-Taha and Dobromir Dobrev. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, University Duisburg-Essen, the Texas Heart Institute and the University of Montreal.
This study is supported by grants from the National Institutes of Health (R01HL164838, R01HL136389, R01HL163277, R01HL131517, R01HL089598, R01HL165704, R01HL127717, R01HL169511 and R01HL171574). Further support was provided by American Heart Association (grants 936111 and 23POST1013888), the European Union (large-scale integrative project MAESTRIA, No. 965286), and the Deutsche Forschungsgemeinschaft (Research Training Group 2989, project 517043330).
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Gasdermin D emerges as a potential therapeutic target for atrial fibrillation
2025-03-27
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