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Review
. 2022 Nov 22:9:1030226.
doi: 10.3389/fmolb.2022.1030226. eCollection 2022.

Exploring the cardiac ECM during fibrosis: A new era with next-gen proteomics

Vivek Sarohi  1   2 , Sanchari Chakraborty  1   2 , Trayambak Basak  1   2
Affiliations
Review

Exploring the cardiac ECM during fibrosis: A new era with next-gen proteomics

Vivek Sarohi et al. Front Mol Biosci. .

Abstract

Extracellular matrix (ECM) plays a critical role in maintaining elasticity in cardiac tissues. Elasticity is required in the heart for properly pumping blood to the whole body. Dysregulated ECM remodeling causes fibrosis in the cardiac tissues. Cardiac fibrosis leads to stiffness in the heart tissues, resulting in heart failure. During cardiac fibrosis, ECM proteins get excessively deposited in the cardiac tissues. In the ECM, cardiac fibroblast proliferates into myofibroblast upon various kinds of stimulations. Fibroblast activation (myofibroblast) contributes majorly toward cardiac fibrosis. Other than cardiac fibroblasts, cardiomyocytes, epithelial/endothelial cells, and immune system cells can also contribute to cardiac fibrosis. Alteration in the expression of the ECM core and ECM-modifier proteins causes different types of cardiac fibrosis. These different components of ECM culminated into different pathways inducing transdifferentiation of cardiac fibroblast into myofibroblast. In this review, we summarize the role of different ECM components during cardiac fibrosis progression leading to heart failure. Furthermore, we highlight the importance of applying mass-spectrometry-based proteomics to understand the key changes occurring in the ECM during fibrotic progression. Next-gen proteomics studies will broaden the potential to identify key targets to combat cardiac fibrosis in order to achieve precise medicine-development in the future.

Keywords: cardiac fibrosis; extracellular matrix; heart failure; mass-spectrometry; proteomics.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Architecture of Cardiac ECM—The figure shows a model transverse section of the myocardium and endocardium layers of the heart. The myocardium layer contains cardiac muscle cells with a basement membrane and the endocardium layer is made up of endothelial cells with a basement membrane. There is an interstitial matrix between the myocardium and endocardium layers. This interstitial space contains fibroblast and extracellular matrix proteins including collagens, elastin, and fibronectin. Different inflammatory cells are also present in the interstitial matrix conditionally.
FIGURE 2
FIGURE 2
Altered cardiac matrisome during cardiac fibrosis—extracellular matrix (ECM) core proteins and ECM-modifier proteins associated with cardiac fibrosis are shown in this figure. The upside arrow (↑) shows up-regulation, and the downside arrow (↓) shows down-regulation. There is a direct or inverse correlation between the level of some ECM proteins during cardiac fibrosis (CF). Versican and TSP1 have been reported to have pro-fibrotic activities.
FIGURE 3
FIGURE 3
Different types of cardiac fibrosis compared with normal myocardium—upon certain profibrotic stimulations, the normal heart turns into a fibrotic one. In reactive interstitial fibrosis, the collagen is increased but the viability of the myocardium persists. In replacement fibrosis, cardiomyocytes are replaced by fibrosis and cardiomyocytes die, and then extensively produced collagen occupies the space of the dead cardiomyocytes and the myocardium fails to perform the contractile function. Infiltrative interstitial fibrosis is found in amyloidosis or Anderson–Fabry disease and there is inflammatory cell infiltration. A new matrix is produced around blood vessels in perivascular fibrosis.
FIGURE 4
FIGURE 4
Summary of the signaling pathways during cardiac fibrosis–the binding of profibrotic factors including TGF-β, Ang-II, PDGF, endothelin-1, and mechanical stress has cascading effects. Activation of Smads leads to the transcription of excessive ECM proteins and pro-fibrotic mediator proteins. Transcription of these myofibroblast phenotypic factors can also be activated by PI3K/Akt, TAK1/P38 MAPK, RAS/Erk MAPK, and RhoA/ROCK pathways.
FIGURE 5
FIGURE 5
Fibrotic niche contributed by several stimuli–the figure shows the various factors contributing to the development of cardiac fibrosis. Effects of various stimuli (cell damage, inflammation, infections toxins, and drugs) on epithelial/endothelial cells can induce cardiac fibrosis either directly via EMT/End MT pathways or indirectly by first activating immune system cells via cytokines. Then, the activated immune system cells secrete profibrotic cytokines leading to the transdifferentiation of cardiac fibroblasts into myofibroblasts. The circulation system also contributes to cardiac fibrosis by entering the profibrotic factors into the cardiac tissues. These profibrotic factors also induce cardiac fibroblasts to myofibroblast transdifferentiation leading to cardiac fibrosis.
FIGURE 6
FIGURE 6
Next-gen proteomics applications to understand cardiac fibrosis—this figure shows the applications of understanding ECM during cardiac diseases using next-gen proteomics. Utilizing next-gen proteomics (protein and PTM analysis) on three biological study types (animal models, cell line models, and clinical human cases) with in silico studies can provide an in-depth understanding of the role of cardiac ECM in the development of cardiac diseases. This understanding will be significantly beneficial in the early diagnosis of cardiac diseases, pathophysiology, and development assessment of cardiac diseases and also in the identification of potential therapeutic agents for cardiac diseases.
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