1Albert- Ludwigs-Universität Freiburg Innere Medizin III, Kardiologie und Angiologie Freiburg im Breisgau, Deutschland; 2Universitäts-Herzzentrum Freiburg - Bad Krozingen Klinik für Kardiologie und Angiologie I Freiburg im Breisgau, Deutschland; 3Universitäts-Herzzentrum Freiburg - Bad Krozingen Freiburg im Breisgau, Deutschland; 4Universitätsklinikum Freiburg Institut für Pharmakologie Freiburg im Breisgau, Deutschland; 5Universitäts-Herzzentrum Freiburg - Bad Krozingen Institut für Experimentelle Kardiovaskuläre Medizin Freiburg im Breisgau, Deutschland; 6Universitäts-Herzzentrum Freiburg - Bad Krozingen Innere Medizin III, Kardiologie und Angiologie Freiburg im Breisgau, Deutschland
Rationale: Although constituting a relatively small population of cells in the heart, macrophages are still important for maintaining cardiac health, for example through efferocytosis of cell debris / exosomes and via electromechanical coupling to cardiomyocytes. Apart from these heterocellular direct interactions, macrophages are exposed to constantly changing mechanical forces in the beating heart. In this project we ask whether and how the stretch-activated ion channel Piezo1 can influence cardiac macrophage phenotypes and myocardial homeostasis.
Methods and results: Macrophage-specific Piezo1 deficient mice (CX3CR1Cre:Piezo1fl/fl, KO) presented no apparent cardiac abnormalities at two months of age. At 6 and 12 months of age, however, KO mice had sponteanously developed an age-related cardiomyopathy with significantly reduced ejection fraction (52.73% WT vs. 45,31% KO; p<0,0001) and lower fractional shortening (27,9% WT vs. 22,89% KO; p<0,0001). Electron microscopic imaging of the murine KO hearts depicted pathological restructuring of cardiomyocytes with mitochondrial dysfunction. In search of the underlying mechanism, we performed high-dimensional single-cell RNA sequencing of sorted CD45+ leukocytes and single-nuclear RNA sequencing of stromal cells in WT and KO mice at 2 and 12 months of age (n=8 per group). Macrophage subclusters with resident cell and foamy cell phenotypes featured the largest number of differentially regulated genes between the groups preceding the development of cardiomyopathy. Genes associated with efferocytosis and regenerative growth factor signalling were reduced in Piezo1 deficient macrophages.
Conclusion: Our preliminary results indicate that mechanosensing by cardiac macrophages is essential to preserve cadiac tissue homeostasis and function during ageing.