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

Thus, cardiac fibrosis is a complex process involving multiple cells and regulated by multiple molecular pathways. Based on this, exosomes derived from various cell types are rich in a variety of miRNAs and proteins and could participate in intercellular communication to mediate cardiac fibrosis process, thus providing a novel strategy for the prediction and treatment of cardiac fibrosis. Cardiac fibrosis, a common pathophysiologic process in most heart diseases, refers to an excess of extracellular matrix deposition by cardiac fibroblasts , which can lead What is Substratum Network 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. 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.

The ETA and ETB receptors, which have been found to perform opposite roles, are two recognized ET-1 receptors in the heart. At first, it was thought that these two receptors were only expressed on endothelial cells; however, the latest evidence suggests that they can also be expressed in other types of cells such as macrophages, cardiomyocytes, and CFs. Furthermore, exosomes derived from cardiomyocytes also exert therapeutic effects in cardiac fibrosis.

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Cardiac fibrosis, a common pathophysiologic event in most heart disease, can lead to poor tissue compliance, hardening of myocardium, and worsening of cardiac dysfunction. CFs, a major cell type of adult myocardium, play a vital role in the process of cardiac fibrosis. MCs, macrophages/monocytes, endothelial cells, and cardiomyocytes, in addition to CFs, also have a role in the fibrotic response through fibrogenic growth factors, the aldosterone/angiotensin axis, or inflammatory signals.

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However, not all types of β-ARs are involved in the profibrotic responses. On the contrary, several studies have proved that, in a model of pressure overload-induced cardiac fibrosis, β3-AR signaling in cardiomyocytes may protect the heart, due to downregulation of the matricellular protein CCN2 by cardiomyocytes. The complexity of interconnections and the extensive range of molecular pathways involved in the fibrotic response have restricted our understanding of the mechanism of cardiac fibrosis. Most fibrotic heart diseases, regardless of cause, appear to include the aldosterone/angiotensin axis and fibrogenic growth factors such as platelet-derived growth factor and TGF-β. Moreover, several inflammatory signals such as TNF-α and IL-6 may regulate reparative and ischemic fibrosis by transducing the cascades of intracellular signaling that result in the transcription of ECM genes and translation of matrix remodeling-related proteins. Here, we demonstrate signaling pathways and mediators known to influence process of cardiac fibrosis after myocardial injury, hoping to find novel therapeutic targets or strategies.

Another research indicated that miR-27a-, miR-28a-, miR-34a-enriched fibroblast-derived exosomes could regulate cardiomyocyte antioxidant enzymes, thus contributing to cardiac hypertrophy . Therefore, exosomes derived from fibroblasts, especially those changing miRNAs contents, are a promising target for cardiac fibrosis. The endothelin family of peptides was mostly known for its vasoconstriction capabilities; however, it is now being recognized for its potential role in tissue fibrosis. ET-1, one of the significant endothelin isoforms in humans, is thought to be secreted predominantly by endothelial cells but also can be produced by other cells including fibroblasts, cardiomyocytes, and macrophages.

  • Additionally, Kang et al. demonstrated that miR-21-loaded human peripheral blood derived-exosomes enhanced fibrosis, making it a novel therapeutic target for cardiac fibrosis .
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  • According to the location of cardiac scars and underlying cause , cardiac fibrosis can be classified into various forms, among which reactive interstitial fibrosis and replacement fibrosis are the most relevant type of the ischemic adult heart.
  • Summary of molecular markers used for the identification of cardiac fibroblasts and myofibroblasts.
  • TGF-β is found in three isoforms (TGF-β1, TGF-β2, and TGF-β3) in mammals , among which TGF-β1 acts as the predominant isoform in the cardiovascular system and expresses ubiquitously.

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Multivesicular bodies , namely, LEs containing these ILVs, can fuse with plasma membrane and release exosomes into the extracellular space or fuse with lysosomes and degrade exosomes . Different cell type- and microenvironment-derived exosomes transport distinct proteins, lipids, and nucleic acid cargoes . Different techniques including microfiltration, gel filtration, ultracentrifugation, and commercial exosomes isolation kits are used to isolate exosomes from body fluids, plasma, or cell culture medium .

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Among these, ultracentrifugation is regarded as the gold standard for exosomes isolation and is also the most common method. Exosomes can enter recipient cells via distinct mechanisms including lipid membrane fusion, internalization by receptor-mediated endocytosis, receptor-mediated binding, and activation of downstream signaling . Total understanding of the biogenesis, isolation, and uptake of exosomes may contribute to find novel strategies for the treatment of cardiac fibrosis. What is more, TGF-β-stimulated myofibroblast transdifferentiation is induced by activation of the Smad3 signaling cascade, which promotes α-SMA transcription in fibroblasts and enhances ECM protein synthesis. Furthermore, cardiomyocyte-specific TβRII knockdown significantly reduced fibrosis in the pressure-overloaded heart , implying that cardiomyocyte-specific TGF-β signaling is essential in the pathogenesis of fibrotic remodeling.

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Evidence indicated that miR-142-3p-enriched exosomes derived from activated CD4+ T cells contributed to the activation of WNT signaling pathway and CF activation, making it a promising target for treating cardiac fibrosis post-MI . MiRNAs, small endogenous oligonucleotides of 21–25 nucleotides, are critical in regulating post-transcriptional gene. Additionally, exosomes, containing different numerous miRNAs, could contribute to or alleviate a variety of pathologies including cardiac fibrosis. Exosomes, derived from distinct cell types including fibroblasts and exogenous MSCs, with upregulation or downregulation of certain miRNAs, can exhibit better ability in attenuating cardiac fibrosis and improving cardiac function . Aldosterone is also capable of inducing fibrotic responses in the myocardium after cardiac injury, suggested by patients with adrenal adenomas and experimental animal studies. Several potential mechanisms have been involved in the profibrotic activities of aldosterone in the heart.

Similar to mining, users who engage in staking earn financial rewards for their work. Adrenergic stimulation causes structural changes in G protein βγ subunits in the damaged myocardium, culminating in activation of G protein-coupled receptor kinase 2 . In an experimental model of MI, GRK2 activation in CFs has been shown to have substantial fibrotic effects. Although the specific fibrotic signals activated by GRK2 remain unclear, GRK2 represents a critical target for therapeutic interventions against cardiac fibrosis. MiRNAs and proteins involved in exosomes for the treatment of cardiac fibrosis.

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However, myocyte-derived HSP90 exerted a profibrotic role through orchestrating the synthesis of IL-6 and activating STAT-3 in fibroblasts, leading to excess collagen secretion and deposition, thus exaggerating cardiac hypertrophy and fibrosis . Emerging evidence indicated that proteins of WNT family are involved in the activation of cardiac fibrotic pathologies (150–152). Działo et al. confirmed that WNT3a-rich exosomes could specifically activate WNT/β-catenin signaling pathway and promoted fibrogenesis in post-infarcted hearts, whereas WNT5a-rich exosomes only activated non-canonical WNT pathways and induced production of profibrotic IL-6 . Summarizing, exosomes containing WNT proteins can regulate cardiac fibrosis via canonical and non-canonical WNT pathways and provide a novel strategy to treat cardiac fibrosis. Taking acute MI as an example, sudden massive loss of cardiomyocytes triggers an intense inflammation and causes the dead myocardium to be replaced with a collagen-based scar , which is critical to prevent cardiac rupture. However, prolonged or excessive fibrotic responses could remarkably lead to excessive ECM deposition, which results in hardening of myocardium, poor tissue compliance, and worsening of cardiac dysfunction.

Molecular Pathways in Cardiac Fibrosis

Furthermore, exosomes via use of a targeting cardiac homing peptide or encapsulated in functional peptide hydrogels exhibit better ability in improving cardiac function and reducing fibrosis . Besides, changes of miRNAs or proteins in exosomes derived from plasma or peripheral blood are considered as novel biomarkers for cardiac fibrosis or cardiac remodeling. Therefore, exosomes could be potential therapeutic treatments in cardiac fibrosis. Thorough knowledge of exosomes and exosome-mediated intercellular communication in cardiac fibrosis will provide better understanding to develop novel strategies for cardiac fibrosis treatments.

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  • However, myocyte-derived HSP90 exerted a profibrotic role through orchestrating the synthesis of IL-6 and activating STAT-3 in fibroblasts, leading to excess collagen secretion and deposition, thus exaggerating cardiac hypertrophy and fibrosis .
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Moreover, endothelin antagonists are now approved to treat pulmonary hypertension, and many believe they will also be beneficial in the treatment of heart pathological fibrosis. Bosentan, a non-selective endothelin receptor antagonist routinely used to treat pulmonary hypertension, has also been shown to reduce fibrotic myocardium remodeling in hypertensive and reparative cardiac fibrosis animal models . Despite the failure of several randomized controlled studies exploring the impact of endothelin antagonists in heart failure and coronary artery disease, manipulating ET-1 signaling appears to be promising. More researches are needed to explore whether ET-1 and its receptors may be appropriate clinically viable anti-fibrotic treatment targets. T4C – Trust 4 Coin shows the most accurate live prices, charts and market rates from trusted top crypto exchanges globally.

The TGF-β family is a group of pleiotropic and multifunctional peptides activated in experimental models of cardiac fibrosis and fibrotic human hearts markedly . TGF-β is found in three isoforms (TGF-β1, TGF-β2, and TGF-β3) in mammals , among which TGF-β1 acts as the predominant isoform in the cardiovascular system and expresses ubiquitously. In the injured heart, TGF-β1, which is present in the normal heart as a latent complex, is transformed from the latent form to the active form via a variety of mediators. Proteases, including MMP-2, MMP-9, and plasmin, are widely acknowledged to participate in the activation of TGF-β as well as the matricellular protein thrombospondin 1 (TSP-1) , which plays an important role in cardiac remodeling. Meanwhile, negative regulation of TGF-β signaling may be crucial in preventing cardiac fibrosis. A study conducted in a mouse model of pressure overload-induced heart failure has suggested that cleavage and release of a soluble endoglin may inhibit fibrogenic actions of TGF-β .

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MCG therapy of mesenchymal stem cells in vitro reduced TGF-β1-mediated transition of MSCs to myofibroblasts, while in vivo delivery of MCGs from rats to the myocardium during AMI lowered fibrosis and enhanced capillary density . These findings suggest that MCs have anti-fibrotic properties and could be used as therapeutic targets in cardiac remodeling. It is recognized that the transdifferentiation from CFs to myofibroblasts is the core cellular event in cardiac fibrosis.

TGF-1 expression is induced by Ang II in fibroblasts and cardiomyocytes via the Ang II type 1 receptor, which plays a crucial role in profibrotic signaling (78–80); and in vivo, TGF-β is necessary for Ang II to induce both cardiac fibrosis and hypertrophy . Besides, Ang II is also intimately involved with the inflammatory response, and in CFs, Ang II enhances their collagen-synthetic activity through extracellular signal-regulated kinase by an IL-6-dependent mechanism indeed. Another mechanism underlying the fibrotic capability of Ang II could involve miR-29b. In vitro, miR-29b suppression promotes Ang II-induced collagen type I and α-SMA expression, but overexpression of miR-29b inhibits it.

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