Myocardial infarction triggers an intense inflammatory reaction that serves to clear the infarct from dead cells and matrix debris. Optimal repair of the infarcted myocardium requires timely resolution of inflammation and activation of endogenous inhibitory pathways that restrain the inflammatory response protecting the infarcted heart from excessive matrix degradation and adverse remodeling. Defects in the STOP signals responsible for containment and resolution of post-infarction inflammation may result in accentuated chamber dilation and contribute to the development of heart failure. Toll-Like Receptor (TLR)/Interleukin (IL)-1 signaling pathways are critical for initiation of the inflammator cascade following tissue injury, but need to be tightly regulated in order to prevent an overactive immunoinflammatory response. We hypothesized that activation of endogenous inhibitory signals is necessary for negative regulation of the TLR/IL-1 response following myocardial infarction, in order to prevent uncontrolled inflammation and to limit dilative remodeling. We will explore two novel pathways responsible for inhibition of the innate immune response in the infarcted myocardium: 1) We have identified Interleukin Receptor Associated Kinase (IRAK)-M, a member of the IRAK-M family that lacks kinase activity, as a key intracellular signal that is upregulated following myocardial infarction and protects the infarcted heart from adverse remodeling restraining inflammation and preventing excessive matrix degradation. IRAK-M expression in infarct macrophages inhibits their inflammatory activity. Our experiments suggest that IRAK-M upregulation in cardiac fibroblasts may limit their matrix-degrading capacity without affecting their inflammatory potential;these effects may be mediated through novel biological interactions between IRAK-M and the TGF-? system. 2) We suggest that dynamic, cell type-specific changes in expression of the signaling type 1 IL-1 receptor (IL-1R1) and of the decoy type 2 receptor (IL-1R2) may play a crucial role in regulation of the inflammatory and reparative response following infarction. Early IL-1R1 upregulation in monocytes/macrophages and in cardiac fibroblasts may induce inflammatory actions, whereas late downregulation of IL-1R1 and induction of the decoy receptor IL-1R2 may serve as a molecular sink terminating IL-1 signaling in the in infarcted myocardium. These concepts will be explored in three specific aims:
Specific aim 1 : to study the role of endogenous IRAK-M upregulation as a protective mechanism that restrains TLR/IL-1-driven inflammation, preventing hyperactive monocyte/macrophage responses and protecting from adverse post- infarction remodeling.
Specific aim 2 : to study the role of IRAK-M in modulating fibroblast phenotype and in regulating matrix remodeling following myocardial infarction and to dissect the pathways responsible for IRAK-M actions in cardiac fibroblasts.
Specific aim 3 : To study the role of cell-type specific changes in expression of signaling and decoy IL-1Rs in regulation of inflammation and repair following myocardial infarction. Our studies will provide new insights into the pathogenesis of adverse remodeling and heart failure following myocardial infarction and may identify new promising therapeutic targets. In addition, the novel effects of IRAK-M on fibroblast function and its potential interactions with the TGF- ? pathway have important implications in the biology of tissue inflammation and repair.

Public Health Relevance

Uncontrolled inflammation after cardiac injury causes damage to the supporting matrix and results in chamber dilation, dysfunction of the heart muscle and progression of cardiac failure. The proposed project explores the role of molecular STOP signals that prevent excessive inflammation and protect the infarcted heart from adverse remodeling and dysfunction

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL085440-06
Application #
8437449
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
2006-06-01
Project End
2017-05-31
Budget Start
2013-06-17
Budget End
2014-05-31
Support Year
6
Fiscal Year
2013
Total Cost
$397,460
Indirect Cost
$159,460
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Chen, Bijun; Frangogiannis, Nikolaos G (2018) The Role of Macrophages in Nonischemic Heart Failure. JACC Basic Transl Sci 3:245-248
Kirk, Jonathan A; Frangogiannis, Nikolaos G (2018) Galectin-3 in the pathogenesis of heart failure: a causative mediator or simply a biomarker? Am J Physiol Heart Circ Physiol 314:H1256-H1258
Shinde, Arti V; Su, Ya; Palanski, Brad A et al. (2018) Pharmacologic inhibition of the enzymatic effects of tissue transglutaminase reduces cardiac fibrosis and attenuates cardiomyocyte hypertrophy following pressure overload. J Mol Cell Cardiol 117:36-48
Frangogiannis, Nikolaos G (2018) Cell biological mechanisms in regulation of the post-infarction inflammatory response. Curr Opin Physiol 1:7-13
Lindsey, Merry L; Bolli, Roberto; Canty Jr, John M et al. (2018) Guidelines for experimental models of myocardial ischemia and infarction. Am J Physiol Heart Circ Physiol 314:H812-H838
Huang, Shuaibo; Frangogiannis, Nikolaos G (2018) Anti-inflammatory therapies in myocardial infarction: failures, hopes and challenges. Br J Pharmacol 175:1377-1400
Alex, Linda; Frangogiannis, Nikolaos G (2018) The Cellular Origin of Activated Fibroblasts in the Infarcted and Remodeling Myocardium. Circ Res 122:540-542
Frangogiannis, Nikolaos G (2018) Cell therapy for peripheral artery disease. Curr Opin Pharmacol 39:27-34
Hanif, Waqas; Alex, Linda; Su, Ya et al. (2017) Left atrial remodeling, hypertrophy, and fibrosis in mouse models of heart failure. Cardiovasc Pathol 30:27-37

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