Cardiac Fibrosis: Cellular Effectors, Molecular Pathways, and Exosomal Roles

Abstract

Cardiac fibrosis, a common pathophysiologic process in most heart diseases, refers to an excess of extracellular matrix (ECM) deposition by cardiac fibroblasts (CFs), which can lead to cardiac dysfunction and heart failure subsequently. Not only CFs but also several other cell types including macrophages and endothelial cells participate in the process of cardiac fibrosis via different molecular pathways. Exosomes, ranging in 30–150 nm of size, have been confirmed to play an essential role in cellular communications by their bioactive contents, which are currently a hot area to explore pathobiology and therapeutic strategy in multiple pathophysiologic processes including cardiac fibrosis. Cardioprotective factors such as RNAs and proteins packaged in exosomes make them an excellent cell-free system to improve cardiac function without significant immune response. Emerging evidence indicates that targeting selective molecules in cell-derived exosomes could be appealing therapeutic treatments in cardiac fibrosis. In this review, we summarize the current understandings of cellular effectors, molecular pathways, and exosomal roles in cardiac fibrosis.

The Scientific Rationale for the Introduction of Renalase in the Concept of Cardiac Fibrosis

“…The proposed relationship between renalase and macrophages deserves to be discussed as a separate section, owing to a few noteworthy macrophage responses incited by renalase, particularly in light of a significant role for monocytes and macrophages as regulators of cardiac fibrosis ( 148 – 155 ). To date, there is substantial evidence that renalase in vivo provides several beneficial effects, such as the hindrance of total macrophage accumulation ( 10 – 13 , 19 , 20 , 47 , 67 , 84 , 102 ), specifically the inflammatory phenotype ( 20 , 84 ), polarizing them toward the M2 phenotype ( 84 ), and blocking inflammasome activation, and IL-1β secretion ( 10 , 47 , 67 ).…”

“…Moreover, possible disorganization between these macrophages’ profiles, according to some authors, represents, at least partially, an underlying mechanism of overwhelmed myocardial inflammation and subsequent cardiac fibrosis ( 1 – 3 , 5 , 6 , 152 – 155 ). To accomplish appropriate evolution from the stage of cardiac tissue repair to a regenerative point, cardiac macrophages most likely have to be supervised, and fine-tuned between pro-fibrotic and anti-fibrotic traits ( 6 , 7 , 151 , 153 ), particularly since macrophages are cells characterized by high plasticity ( 3 , 5 , 6 , 31 , 32 , 148 – 155 ), whose functions may be context-dependent (steady-state or injury). In line with that, it is confirmed that during the proliferative phase, a macrophage’s modulation aims to boost the M2-phenotype, and deplete M1-macrophages, and results in a significant lessening of interstitial cardiac fibrosis ( 3 , 5 , 6 , 154 ).…”

Diagnostic and Therapeutic Properties of Exosomes in Cardiac Fibrosis

“…Exosomes have a circular single-membrane structure and range between 30 and 150 nm in size. They are formed by a series of regulated processes such as endocytosis-fusion-exocytosis ( Raposo & Stoorvogel, 2013 ; Zaborowski et al, 2015 ; Nguyen et al, 2016 ; Jiang et al, 2021 ). Early endosomes are formed by invagination of the cell membrane and subsequently mature into multivesicular bodies (MVBs) ( Raposo & Stoorvogel, 2013 ; Yáñez-Mó et al, 2015 ).…”

“…Although numerous pathogenic factors have been identified, the specific mechanisms underlying its development are unclear and require further investigation. Exosomes are small vesicles (30–150 nm in size) secreted by cells that play an essential role in intercellular communication ( Zaborowski et al, 2015 ; Jiang et al, 2021 ), mediated by a class of proteins and nucleic acids carried within the exosomes that are transported from cell to cell ( Zamani et al, 2019 ). Under disease conditions, fibroblasts, cardiomyocytes, macrophages, lymphocytes, and vascular endothelial cells communicate with each other through exosomes and their cargoes, ultimately leading to myocardial fibrosis ( Jiang et al, 2021 ).…”

“…Exosomes are small vesicles (30–150 nm in size) secreted by cells that play an essential role in intercellular communication ( Zaborowski et al, 2015 ; Jiang et al, 2021 ), mediated by a class of proteins and nucleic acids carried within the exosomes that are transported from cell to cell ( Zamani et al, 2019 ). Under disease conditions, fibroblasts, cardiomyocytes, macrophages, lymphocytes, and vascular endothelial cells communicate with each other through exosomes and their cargoes, ultimately leading to myocardial fibrosis ( Jiang et al, 2021 ). In recent years, although exosomes have been reported to be involved in the diagnosis and treatment of a variety of diseases, their role in myocardial fibrosis is less well understood.…”