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Review
. 2014 May:70:74-82.
doi: 10.1016/j.yjmcc.2013.11.015. Epub 2013 Dec 7.

Fibroblasts in myocardial infarction: a role in inflammation and repair

Arti V Shinde  1 , Nikolaos G Frangogiannis  2
Affiliations
Review

Fibroblasts in myocardial infarction: a role in inflammation and repair

Arti V Shinde et al. J Mol Cell Cardiol. 2014 May.

Abstract

Fibroblasts do not only serve as matrix-producing reparative cells, but exhibit a wide range of functions in inflammatory and immune responses, angiogenesis and neoplasia. The adult mammalian myocardium contains abundant fibroblasts enmeshed within the interstitial and perivascular extracellular matrix. The current review manuscript discusses the dynamic phenotypic and functional alterations of cardiac fibroblasts following myocardial infarction. Extensive necrosis of cardiomyocytes in the infarcted heart triggers an intense inflammatory reaction. In the early stages of infarct healing, fibroblasts become pro-inflammatory cells, activating the inflammasome and producing cytokines, chemokines and proteases. Pro-inflammatory cytokines (such as Interleukin-1) delay myofibroblast transformation, until the wound is cleared from dead cells and matrix debris. Resolution of the inflammatory infiltrate is associated with fibroblast migration, proliferation, matrix protein synthesis and myofibroblast conversion. Growth factors and matricellular proteins play an important role in myofibroblast activation during the proliferative phase of healing. Formation of a mature cross-linked scar is associated with clearance of fibroblasts, as poorly-understood inhibitory signals restrain the fibrotic response. However, in the non-infarcted remodeling myocardium, local fibroblasts may remain activated in response to volume and pressure overload and may promote interstitial fibrosis. Considering their abundance, their crucial role in cardiac inflammation and repair, and their involvement in myocardial dysfunction and arrhythmogenesis, cardiac fibroblasts may be key therapeutic targets in cardiac remodeling. This article is part of a Special Issue entitled Myocyte-Fibroblast Signalling in Myocardium.

Keywords: Cardiac remodeling; Extracellular matrix; Fibroblast; Inflammation; Myocardial infarction; Transforming growth factor (TGF)-β.

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Figures

Figure 1
Figure 1
Myofibroblasts in healing myocardial infarction. A–C: Immunohistochemical staining for α-smooth muscle actin (SMA) in control canine myocardium (A) and in infarcted hearts (B – 1h coronary occlusion/7days reperfusion; C – 1h occlusion/28days reperfusion). In control hearts, α-SMA is expressed exclusively by vascular mural cells. After 7 days of reperfusion, abundant spindle-shaped α-SMA+ myofibroblasts are noted in the infarct border zone (arrows). After 28 days of reperfusion, border zone myofibroblasts are markedly reduced and α-SMA immunoreactivity is localized in vascular mural cells (arrowheads).
Figure 2
Figure 2
During the early stages following myocardial infarction cardiac fibroblasts become inflammatory cells. Infarct fibroblasts activate the inflammasome, a multimolecule complex that cleaves pro-IL-1β leading to secretion of the active cytokine. Reactive oxygen species (ROS), cytokines (such as IL-1β and TNF-α) and matrix fragments induce fibroblast inflammatory activation and promote a matrix-degrading phenotype. IL-1β suppresses α-smooth muscle actin expression delaying myofibroblast conversion.
Figure 3
Figure 3
During the proliferative phase of cardiac repair, fibroblasts undergo myofibroblast transdifferentiation expressing contractile proteins and secreting large amounts of matrix proteins. Growth factors, the renin-angiotensin-aldosterone axis, and the mast cell-derived proteases tryptase and chymase are implicated in myofibroblast transformation and proliferation, and stimulate matrix protein synthesis. Specialized matrix proteins contribute to fibroblast activation.
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