Left ventricular remodeling after myocardial infarction leads to heart failure, a predominant cause of death worldwide. Basic cellular-scale mechanisms contributing to the generation of heart failure include myocyte hypertrophy and apoptosis, heightened protease release leading to extracellular matrix degradation and ventricular dilation, and fibrosis caused by myofibroblasts, among others. We have recently reported a novel observation in mice and patients: inflammatory myeloid cells (monocytes, macrophages) invade not only the acutely ischemic myocardium but also the remote zone after MI. Strikingly, we have detected their presence in failing non-ischemic myocardium months after MI, reflecting chronic inflammation. Their known functions in other chronic inflammatory conditions such as atherosclerosis and autoimmune disease position myeloid cells as master orchestrators of tissue remodeling, as they release pro-inflammatory cytokines, carry a high protease payload, and instigate fibrosis. The role of myeloid cells in the failing myocardium; however, is unknown. Our preliminary data show that macrophages in failing hearts are descendants of inflammatory CCR2+ monocytes, and that their neutralization attenuates post-MI remodeling. We thus hypothesize that myocardial leukocyte presence may reflect a cause -- and new therapeutic point of attack -- for post-MI heart failure. We will study leukocyte's presence, phenotype, subsets and their impact on disease progression. We hypothesize that myeloid cells instruct resident cells, including fibroblasts, myocytes, and endothelial cells with pro-inflammatory and pro-fibrotic signals and are a source of matrix-degrading proteases. To investigate patrolling, recruitment, and cross-talk of leukocytes to parenchymal cells in the remote myocardium, we will follow immune cell's behavior in their undisturbed microenvironment with in vivo multi-channel fluorescence microscopy of the beating heart. Gene expression studies of cells isolated from the remote zone will yield their key signals. We will use in vivo RNAi therapy to knock down CCR2 in circulating monocytes, thus limiting their recruitment and the detrimental effect of monocyte-derived macrophages on post-MI remodeling. Phenotyping will employ multi-scale imaging with intravital microscopy, fluorescence molecular tomography, cine and tagging magnetic resonance imaging.
We will test the hypothesis that myeloid cells recruited to the heart instigate left ventricular remodeling after coronary ligation in mice. We will study leukocyte's presence, phenotype, subsets and their impact on disease progression. We investigate how monocytes/macrophages instruct parenchymal cardiac cells during evolution of heart failure, including fibroblasts, myocytes, and endothelial cells.
| Hulsmans, Maarten; Sager, Hendrik B; Roh, Jason D et al. (2018) Cardiac macrophages promote diastolic dysfunction. J Exp Med 215:423-440 |
| Honold, Lisa; Nahrendorf, Matthias (2018) Resident and Monocyte-Derived Macrophages in Cardiovascular Disease. Circ Res 122:113-127 |
| Keliher, Edmund J; Ye, Yu-Xiang; Wojtkiewicz, Gregory R et al. (2017) Polyglucose nanoparticles with renal elimination and macrophage avidity facilitate PET imaging in ischaemic heart disease. Nat Commun 8:14064 |
| Frodermann, Vanessa; Nahrendorf, Matthias (2017) Neutrophil-macrophage cross-talk in acute myocardial infarction. Eur Heart J 38:198-200 |
| Lee, Sungon; Courties, Gabriel; Nahrendorf, Matthias et al. (2017) Motion characterization scheme to minimize motion artifacts in intravital microscopy. J Biomed Opt 22:36005 |
| Vandoorne, Katrien; Nahrendorf, Matthias (2017) Multiparametric Imaging of Organ System Interfaces. Circ Cardiovasc Imaging 10: |
| Hulsmans, Maarten; Clauss, Sebastian; Xiao, Ling et al. (2017) Macrophages Facilitate Electrical Conduction in the Heart. Cell 169:510-522.e20 |
| King, Kevin R; Aguirre, Aaron D; Ye, Yu-Xiang et al. (2017) IRF3 and type I interferons fuel a fatal response to myocardial infarction. Nat Med 23:1481-1487 |
| Sager, Hendrik B; Hulsmans, Maarten; Lavine, Kory J et al. (2016) Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure. Circ Res 119:853-64 |
| Dutta, Partha; Hoyer, Friedrich Felix; Sun, Yuan et al. (2016) E-Selectin Inhibition Mitigates Splenic HSC Activation and Myelopoiesis in Hypercholesterolemic Mice With Myocardial Infarction. Arterioscler Thromb Vasc Biol 36:1802-8 |
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