Healing of the infarcted heart is dependent on an inflammatory reaction that serves to clear the wound from dead cells and matrix debris, while activating reparative pathways. Transforming Growth Factor (TGF)- is induced and activated in the infarcted myocardium and critically regulates the reparative, fibrotic and remodeling responses through cell-specific actions that involve a family of intracellular effectors, the Smads TGF- may also signal through activation of Smad-independent pathways. Targeting TGF- in infarcted and failing hearts holds therapeutic promise; however, implementation of such approaches requires dissection of the cellular effects of Smad and non-Smad signaling cascades. This competing renewal application studies the role of TGF- signaling pathways in the infarcted heart. Using cell-specific knockout mice and in vitro strategies we will explore the cell biological effects and functional consequences of TGF-/Smad signaling in the remodeling infarcted myocardium. Our unpublished preliminary data suggest crucial and distinct effects of Smad-dependent signaling on cardiomyocytes, fibroblasts and macrophages; these actions have opposing effects on post-infarction cardiac remodeling. Our experiments will dissect the role of Smad2 and Smad3 signaling in fibroblasts, macrophages and cardiomyocytes:
Specific aim 1 will study the in vivo role of fibroblast-specific Smad-dependent signaling in repair and remodeling of the infarcted heart. Using mice with cell-specific loss of Smad2 or Smad3 in activated myofibroblasts (generated by our laboratory), we will investigate the role of fibroblast Smad signaling in repair, remodeling and function of the infarcted heart and we will dissect the molecular basis for Smad-dependent actions.
Specific aim 2 will dissect the effects of Smad-dependent and non-Smad signaling on cardiac fibroblast phenotype and function. Cardiac fibroblasts will be cultured in collagen pads in order to explore and dissect cell:matrix interactions.
Specific aim 3 will investigate the role of macrophage Smad2 and Smad3 signaling in repair and remodeling of the infarcted heart using mice with cell-specific loss of Smad2/3. Moreover, in vitro studies will investigate the effects of Smad cascades on macrophage differentiation, phenotype, and function.
Specific aim 4 will study the role of cardiomyocyte-specific Smad2 and Smad3 in injury, repair and remodeling of the infarcted heart using cell-specific KOs. Cardiomyocyte Smad signaling may modulate apoptotic cascades, may trigger a hypertrophic program, or may mediate paracrine actions of cardiomyocytes, responsible for adverse remodeling.

Public Health Relevance

Transforming Growth Factor (TGF)- is a crucial regulator of inflammatory and fibrotic processes and exerts important actions on all cell types involved in the reparative response following myocardial infarction. The current proposal explores the role of TGF- -activated Smad2/3 signaling in repair and remodeling of the infarcted heart. Using in vivo and in vitro experiments, we will dissect the cellular effects of Smad-dependent cascades on fibroblast, macrophage and cardiomyocyte phenotype and function in the infarcted and remodeling heart.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Schwartz, Lisa
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Albert Einstein College of Medicine, Inc
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Shinde, Arti V; Humeres, Claudio; Frangogiannis, Nikolaos G (2017) The role of ?-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling. Biochim Biophys Acta 1863:298-309
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
Shinde, Arti V; Frangogiannis, Nikolaos G (2017) Mechanisms of Fibroblast Activation in the Remodeling Myocardium. Curr Pathobiol Rep 5:145-152
Frangogiannis, Nikolaos G (2016) The Functional Pluralism of Fibroblasts in the Infarcted Myocardium. Circ Res 119:1049-1051
Chen, Bijun; Frangogiannis, Nikolaos G (2016) Macrophages in the Remodeling Failing Heart. Circ Res 119:776-8
Saxena, Amit; Russo, Ilaria; Frangogiannis, Nikolaos G (2016) Inflammation as a therapeutic target in myocardial infarction: learning from past failures to meet future challenges. Transl Res 167:152-66
Frangogiannis, Nikolaos G (2016) Fibroblast-Extracellular Matrix Interactions in Tissue Fibrosis. Curr Pathobiol Rep 4:11-18
Spinale, Francis G; Frangogiannis, Nikolaos G; Hinz, Boris et al. (2016) Crossing Into the Next Frontier of Cardiac Extracellular Matrix Research. Circ Res 119:1040-1045
Frunza, Olga; Russo, Ilaria; Shinde, Arti V et al. (2016) Authors' Reply. Am J Pathol 186:2234-2235
Prabhu, Sumanth D; Frangogiannis, Nikolaos G (2016) The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis. Circ Res 119:91-112

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