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Updated: May 15, 2026
Programmed Electrical Stimulation in Mice
Published on: May 26, 2010
Macrophage IL-1β mediates atrial fibrillation risk in diabetic mice
Abstract:
Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). The mechanisms underlying DM-associated AF are unclear. AF and DM are both related to inflammation. We investigated whether DM-associated inflammation contributed to AF risk. Mice were fed with high-fat diet to induce type II DM and were subjected to IL-1β antibodies, macrophage depletion by clodronate liposomes, a mitochondrial antioxidant (mitoTEMPO), or a cardiac ryanodine receptor 2 (RyR2) stabilizer (S107). All tests were performed at 36-38 weeks of age. DM mice presented with increased AF inducibility, enhanced mitochondrial reactive oxygen species (mitoROS) generation, and activated innate immunity in the atria, as evidenced by enhanced monocyte chemoattractant protein-1 (MCP-1) expression, macrophage infiltration, and IL-1β levels. Signs of aberrant RyR2 Ca2+ leak were observed in the atria of DM mice. IL-1β neutralization, macrophage depletion, and exposure to mitoTEMPO and S107 significantly ameliorated the AF vulnerability in DM mice. Atrial overexpression of MCP-1 increased AF occurrence in normal mice through the same mechanistic signaling cascade as observed in DM mice. In conclusion, macrophage-mediated IL-1β contributed to DM-associated AF risk through mitoROS modulation of RyR2 Ca2+ leak.
Insights
Diabetes mellitus increases atrial fibrillation risk through inflammation. Macrophage-driven IL-1β, mitochondrial ROS, and RyR2 Ca2+ leak in the atria contribute to this risk, but treatments targeting these pathways show promise.
Area of Science:
- Cardiovascular Disease
- Metabolic Disorders
- Immunology
Background:
- Diabetes mellitus (DM) is a known risk factor for atrial fibrillation (AF).
- The precise mechanisms linking DM and AF remain incompletely understood.
- Both DM and AF share inflammatory pathways.
Purpose of the Study:
- To investigate the role of DM-associated inflammation in AF development.
- To elucidate the specific molecular mechanisms involved in DM-induced AF.
Main Methods:
- Type II DM was induced in mice using a high-fat diet.
- Mice were treated with IL-1β antibodies, clodronate liposomes (macrophage depletion), mitoTEMPO, or S107.
- Measurements included AF inducibility, mitochondrial reactive oxygen species (mitoROS), and atrial inflammatory markers.
Main Results:
- DM mice exhibited increased AF inducibility, elevated mitoROS, and heightened atrial inflammation (MCP-1, macrophages, IL-1β).
- Aberrant cardiac ryanodine receptor 2 (RyR2) Ca2+ leak was observed in DM mice atria.
- Treatments targeting IL-1β, macrophages, mitoROS, or RyR2 Ca2+ leak significantly reduced AF vulnerability.
Conclusions:
- Macrophage-mediated IL-1β contributes to DM-associated AF risk.
- This pathway involves modulation of mitoROS and subsequent RyR2 Ca2+ leak.
- Targeting these inflammatory and molecular mechanisms may offer therapeutic strategies for AF in diabetic patients.
