Effective repair of the infarcted heart depends on mechanisms that suppress the inflammatory response after granulation tissue formation has occurred, and that limit expansion of fibrosis to the non-infarcted myocardium. Our project examines the mechanisms responsible for resolution of post-infarction inflammation and transition to fibrous tissue deposition. Our preliminary experiments suggest that Thrombospondin (TSP)-1, a potent angiostatic mediator and crucial TGF-2 activator, and the matrix crosslinking enzyme tissue transglutaminase (tTG), are selectively induced in the infarct border zone and that TSP-1 plays a key role in suppression of the chemokine response and resolution of the inflammatory infiltrate in healing infarcts. The selective localization of TSP-1 and tTG suggests that, through its unique composition, the infarct border zone may serve as a barrier preventing expansion of granulation tissue formation into the non- infarcted myocardium.
Specific aim 1 will examine the role of TSP-1 in suppression and containment of the post-infarction inflammatory response. In vivo experiments examining activation of TGF-2 signaling pathways and neovessel formation, in vitro studies using endothelial cells and infarct myofibroblasts isolated from TSP-1 -/- and WT mice and injections of peptides that restore specific actions of the TSP-1 molecule will be used to examine the mechanistic basis of the TSP-1-mediated effects.
Specific aim 2 will test the hypothesis that tTG may protect the non-infarcted myocardium by locally activating TGF- beta and by forming a "barrier" composed of proteolysis-resistant matrix, preventing leukocyte migration. In vivo studies using tTG -/- mice and in vitro experiments using infarct myofibroblasts and endothelial cells from WT and tTG -/- mice will be performed.
Specific aim 3 will explore the signaling pathways responsible for the distinct effects of TGF-2 in suppressing inflammation by repressing chemokine and cytokine expression in endothelial cells, and in promoting fibrosis, by inducing extracellular matrix proteins and by altering the MMP:TIMP balance in cardiac fibroblasts. The importance of Smad- dependent and Smad-independent pathways in post-infarction inflammation and fibrous tissue deposition will be examined using myocardial infarction experiments and in vitro studies on isolated endothelial cells and fibroblasts. These studies may lead to therapeutic interventions aimed at optimizing cardiac repair by preventing prolongation and extension of the inflammatory injury.
|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|
|Shinde, Arti V; Frangogiannis, Nikolaos G (2014) Fibroblasts in myocardial infarction: a role in inflammation and repair. J Mol Cell Cardiol 70:74-82|
|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|
|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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