It has been hypothesized that IL-1α is released from damaged cardiomyocytes following myocardial infarction (MI) and activates cardiac fibroblasts via its receptor (IL-1R1) to drive the early stages of cardiac remodeling. This study aimed to definitively test this hypothesis using cell type–specific IL-1α and IL-1R1–KO mouse models. A floxed Il1a mouse was created and used to generate a cardiomyocyte-specific IL-1α–KO (MIL1AKO) mouse line. A tamoxifen-inducible fibroblast-specific IL-1R1 hemizygous KO (FIL1R1KO) mouse line was also generated. Mice underwent experimental MI (permanent left anterior descending coronary artery ligation), and cardiac function was determined 4 weeks later by conductance pressure-volume catheter analysis. Molecular markers of remodeling were evaluated at various time points by real-time RT-PCR and histology. MIL1AKO mice showed no difference in cardiac function or molecular markers of remodeling after MI compared with littermate controls. In contrast, FIL1R1KO mice showed improved cardiac function and reduced remodeling markers after MI compared with littermate controls. In conclusion, these data highlight a key role for the IL-1R1/cardiac fibroblast signaling axis in regulating remodeling after MI and provide support for the continued development of anti–IL-1 therapies for improving cardiac function after MI. Cardiomyocyte-derived IL-1α was not an important contributor to remodeling after MI in this model.
Sumia A. Bageghni, Karen E. Hemmings, Nadira Y. Yuldasheva, Azhar Maqbool, Filomena O. Gamboa-Esteves, Neil E. Humphreys, Maj Simonsen Jackson, Christopher P. Denton, Sheila Francis, Karen E. Porter, Justin F.X. Ainscough, Emmanuel Pinteaux, Mark J. Drinkhill, Neil A. Turner
Creation, characterization, and functional assessment of cardiomyocyte-specific IL-1α–KO mouse line (MIL1AKO).