Chemokine-driven inflammation plays an important role in the reparative response following myocardial infarction and is critically involved in the pathogenesis of adverse remodeling. Differential expression of chemokine receptors by monocyte and lymphocyte subsets governs their trafficking in the infarcted myocardium resulting in infiltration with subpopulations that exhibit distinct functional properties. We propose that beyond their involvement in initiation and activation of the post-infarction inflammatory reaction, chemokine-mediated interactions also play an important role in suppression of inflammation through recruitment of leukocyte subsets with inhibitory properties. Our studies suggest that signaling through the CC chemokine receptor 5 (CCR5) mediates recruitment of suppressive monocyte subsets and regulatory T cells (Tregs), a CD4+ T lymphocyte subpopulation with an essential role in regulation of immune responses. Accordingly, the objective of the current proposal is to investigate the role of Tregs and inhibitory monocyte subpopulations in regulation of post-infarction inflammation, to study the molecular signals responsible for their protective effects, and to explore the role of chemokine signaling in their recruitment in the infarcted myocardium. These concepts will be examined in three specific aims:
Specific aim 1 : to investigate the role of monocyte subsets with anti-inflammatory properties in controlling the post-infarction inflammatory response.
Specific aim 2 : to study the involvement of Tregs in inhibition of inflammatory injury, in prevention of excessive matrix degradation and in protection from the development of adverse remodeling following myocardial infarction.
Specific aim 3 : to investigate chemokine/chemokine receptor interactions responsible for recruitment of Tregs and effector T cells in the infarcted myocardium. Chemokine-mediated suppression of inflammation through recruitment of regulatory mononuclear cell subpopulations appears to play an essential role in cardiac repair and protects from the development of adverse remodeling. Understanding the effects of inhibitory monocytes and Tregs may identify novel therapeutic targets for pharmacologic interventions and cell therapy in patients with myocardial infarction.

Public Health Relevance

The proposed project explores the role of monocyte subsets and regulatory T cells in preventing uncontrolled inflammation and excessive injury in myocardial infarction. Chemokine-mediated interactions responsible for recruitment of suppressive mononuclear cell subpopulations may play an essential protective role in the pathogenesis of adverse cardiac remodeling. The findings may identify novel therapeutic targets for pharmacologic interventions and cell therapy in patients with acute myocardial infarction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076246-09
Application #
8443442
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
2004-04-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
9
Fiscal Year
2013
Total Cost
$395,080
Indirect Cost
$157,080
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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Frangogiannis, Nikolaos G (2014) The immune system and the remodeling infarcted heart: cell biological insights and therapeutic opportunities. J Cardiovasc Pharmacol 63:185-95
Frangogiannis, Nikolaos G (2014) The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol 11:255-65
Cavalera, Michele; Wang, Junhong; Frangogiannis, Nikolaos G (2014) Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities. Transl Res 164:323-35
Kong, Ping; Christia, Panagiota; Frangogiannis, Nikolaos G (2014) The pathogenesis of cardiac fibrosis. Cell Mol Life Sci 71:549-74
Frangogiannis, Nikolaos G (2014) Contribution of extramedullary organs in myocardial inflammation and remodeling: does the spleen cause cardiac melancholy? Circ Res 114:230-2
Saxena, Amit; Bujak, Marcin; Frunza, Olga et al. (2014) CXCR3-independent actions of the CXC chemokine CXCL10 in the infarcted myocardium and in isolated cardiac fibroblasts are mediated through proteoglycans. Cardiovasc Res 103:217-27
Cavalera, Michele; Frangogiannis, Nikolaos G (2014) Targeting the chemokines in cardiac repair. Curr Pharm Des 20:1971-9
Christia, Panagiota; Frangogiannis, Nikolaos G (2013) Targeting inflammatory pathways in myocardial infarction. Eur J Clin Invest 43:986-95
Christia, Panagiota; Bujak, Marcin; Gonzalez-Quesada, Carlos et al. (2013) Systematic characterization of myocardial inflammation, repair, and remodeling in a mouse model of reperfused myocardial infarction. J Histochem Cytochem 61:555-70

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