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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01HL117829-01A1
Application #
8626617
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Desvigne-Nickens, Patrice
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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
Swirski, Filip K; Robbins, Clinton S; Nahrendorf, Matthias (2016) Development and Function of Arterial and Cardiac Macrophages. Trends Immunol 37:32-40
Nahrendorf, Matthias; Swirski, Filip K (2016) Innate immune cells in ischaemic heart disease: does myocardial infarction beget myocardial infarction? Eur Heart J 37:868-72
Hulsmans, Maarten; Sam, Flora; Nahrendorf, Matthias (2016) Monocyte and macrophage contributions to cardiac remodeling. J Mol Cell Cardiol 93:149-55
Sager, Hendrik B; Dutta, Partha; Dahlman, James E et al. (2016) RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction. Sci Transl Med 8:342ra80
Nahrendorf, Matthias; Swirski, Filip K (2016) Abandoning M1/M2 for a Network Model of Macrophage Function. Circ Res 119:414-7
Dutta, Partha; Sager, Hendrik B; Stengel, Kristy R et al. (2015) Myocardial Infarction Activates CCR2(+) Hematopoietic Stem and Progenitor Cells. Cell Stem Cell 16:477-87
Nahrendorf, Matthias; Frantz, Stefan; Swirski, Filip K et al. (2015) Imaging systemic inflammatory networks in ischemic heart disease. J Am Coll Cardiol 65:1583-91
Sager, Hendrik B; Heidt, Timo; Hulsmans, Maarten et al. (2015) Targeting Interleukin-1β Reduces Leukocyte Production After Acute Myocardial Infarction. Circulation 132:1880-90
Leuschner, Florian; Courties, Gabriel; Dutta, Partha et al. (2015) Silencing of CCR2 in myocarditis. Eur Heart J 36:1478-88

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