Cardiac fibrosis: new insights into the pathogenesis

Zhen-Guo Ma, Yu-Pei Yuan, Hai-Ming Wu, Xin Zhang, Qi-Zhu Tang, Zhen-Guo Ma, Yu-Pei Yuan, Hai-Ming Wu, Xin Zhang, Qi-Zhu Tang

Abstract

Cardiac fibrosis is defined as the imbalance of extracellular matrix (ECM) production and degradation, thus contributing to cardiac dysfunction in many cardiac pathophysiologic conditions. This review discusses specific markers and origin of cardiac fibroblasts (CFs), and the underlying mechanism involved in the development of cardiac fibrosis. Currently, there are no CFs-specific molecular markers. Most studies use co-labelling with panels of antibodies that can recognize CFs. Origin of fibroblasts is heterogeneous. After fibrotic stimuli, the levels of myocardial pro-fibrotic growth factors and cytokines are increased. These pro-fibrotic growth factors and cytokines bind to its receptors and then trigger the activation of signaling pathway and transcriptional factors via Smad-dependent or Smad independent-manners. These fibrosis-related transcriptional factors regulate gene expression that are involved in the fibrosis to amplify the fibrotic response. Understanding the mechanisms responsible for initiation, progression, and amplification of cardiac fibrosis are of great clinical significance to find drugs that can prevent the progression of cardiac fibrosis.

Keywords: Cardiac fibroblast; Cardiac fibrosis; Smad; TGF-β.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Schematic displaying the serviceable fibroblast markers. Vimentin is a constituent of the intermediate-filament family of proteins and used to identify the purity of isolated cardiac fibroblasts in vitro. Upon stimuli, interstitial fibroblasts would express α-smooth muscle actin (α-SMA), a sign of fibroblasts activation. Fibroblast-specific protein 1 (FSP1) is also specific for fibroblasts in the heart. Domain receptor (DDR) 2, a membrane tyrosine kinase receptor, can label a part of fibroblasts in the heart. Periostin is a secreted protein and specifically expressed by all newly activated fibroblasts (myofibroblasts) upon heart injury without ectopic expression in other cardiac cell types.
Figure 2
Figure 2
Origins of cardiac fibroblasts. Schematic demonstrates the origins of fibroblasts in the heart. Normal heart only has resident fibroblasts. Upon stimuli, resident fibroblasts proliferates. Endothelial cells, bone marrow cells and epicardium contribute to the total pool of fibroblasts. In response to stimuli, cardiomyocytes become hypertrophy and muscle fibers become disarranged.
Figure 3
Figure 3
Fibrotic signaling mechanisms between different cardiac populations. Fibrosis can be augmented by proinflammatory cytokines and profibrotic and molecules. Angiotensin II, Ang II; AT1, angiotensin II type 1; extracellular matrix, ECM; interleukin, IL; transforming growth factor-β, TGF-β; TGF-β receptor, TβR.
Figure 4
Figure 4
Transforming growth factor-β (TGF-β) signaling pathway through Smad-dependent and Smad-independent pathways. TGF-β induced the translocation of Smad2 and Smad3 complex into nucleus to amplify the fibrotic response. Apart from this, MAPK, AKT and AMPK were also activated during fibrotic response.

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