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Cardiac Fibrosis: Molecular Pathology and Therapeutics

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 12482

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Special Issue Editor

Dr. Michael Czubryt

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Guest Editor

Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
Interests: heart failure; cardiac fibrosis; gene regulation; transcription; epigenetics; myocardial infarction; hypertension; wound healing

Special Issue Information

Dear Colleagues,

Cardiac fibrosis is a pathological hallmark of a broad range of cardiovascular diseases, including hypertension and myocardial infarction. Remodeling of the cardiac extracellular matrix—including increased synthesis, decreased degradation, and/or altered structure—is not only indicative of underlying disease but itself significantly impairs systolic and diastolic function, contributes to arrhythmogenesis and heart failure, and increases patient morbidity and mortality. Despite many years of concerted effort, therapies remain elusive, with no clinically approved medications presently available for patient care. Interest in understanding and managing cardiac fibrosis has exploded in the past decade, and with a rapidly growing body of new research into its pathobiology, there is new optimism that treatments will be developed to reduce the patient burden.

This Special Issue of IJMS examines the underlying mechanisms contributing to cardiac fibrosis, focusing in particular on novel contributors to the initiation, progression, and resolution of fibrosis, and in so doing, provides insight into potential novel therapeutic targets. Such studies are urgently needed to finally start bringing relief to patients who currently lack effective treatment options.

Since IJMS is a journal of molecular science, pure clinical studies are not suitable for our journal. However, clinical or pure model submissions with biomolecular experiments are welcomed.

Dr. Michael Czubryt
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

heart failure
fibrosis
cardiomyopathy
transcription
epigenetics
myocardial infarction

Published Papers (6 papers)

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Research

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17 pages, 3650 KiB

Open AccessArticle

Identification of Gene Expression Signatures for Phenotype-Specific Drug Targeting of Cardiac Fibrosis

by Dominika Lukovic, Ena Hasimbegovic, Johannes Winkler, Julia Mester-Tonczar, Katrin Müller-Zlabinger, Emilie Han, Andreas Spannbauer, Denise Traxler-Weidenauer, Jutta Bergler-Klein, Noemi Pavo, Georg Goliasch, Sandor Batkai, Thomas Thum, Faiez Zannad and Mariann Gyöngyösi

Int. J. Mol. Sci. 2023, 24(8), 7461; https://doi.org/10.3390/ijms24087461 - 18 Apr 2023

Viewed by 1638

Abstract

We have designed translational animal models to investigate cardiac profibrotic gene signatures. Domestic pigs were treated with cardiotoxic drugs (doxorubicin, DOX, n = 5 or Myocet^®, MYO, n = 5) to induce replacement fibrosis via cardiotoxicity. Reactive interstitial fibrosis was triggered by LV pressure overload by artificial isthmus stenosis with stepwise developing myocardial hypertrophy and final fibrosis (Hyper, n = 3) or by LV volume overload in the adverse remodeled LV after myocardial infarction (RemoLV, n = 3). Sham interventions served as controls and healthy animals (Control, n = 3) served as a reference in sequencing study. Myocardial samples from the LV of each group were subjected to RNA sequencing. RNA-seq analysis revealed a clear distinction between the transcriptomes of myocardial fibrosis (MF) models. Cardiotoxic drugs activated the TNF-alpha and adrenergic signaling pathways. Pressure or volume overload led to the activation of FoxO pathway. Significant upregulation of pathway components enabled the identification of potential drug candidates used for the treatment of heart failure, such as ACE inhibitors, ARB, ß-blockers, statins and diuretics specific to the distinct MF models. We identified candidate drugs in the groups of channel blockers, thiostrepton that targets the FOXM1-regulated ACE conversion to ACE2, tyrosine kinases or peroxisome proliferator-activated receptor inhibitors. Our study identified different gene targets involved in the development of distinct preclinical MF protocols enabling tailoring expression signature-based approach for the treatment of MF. Full article

(This article belongs to the Special Issue Cardiac Fibrosis: Molecular Pathology and Therapeutics)

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18 pages, 4477 KiB

Open AccessArticle

Endothelin-1 Induces Cell Proliferation and Myofibroblast Differentiation through the ET_AR/G_αq/ERK Signaling Pathway in Human Cardiac Fibroblasts

by Ratchanee Duangrat, Warisara Parichatikanond, Sutharinee Likitnukul and Supachoke Mangmool

Int. J. Mol. Sci. 2023, 24(5), 4475; https://doi.org/10.3390/ijms24054475 - 24 Feb 2023

Cited by 4 | Viewed by 1961

Abstract

Endothelin-1 (ET-1) has been implicated in the pathogenesis of cardiac fibrosis. Stimulation of endothelin receptors (ETR) with ET-1 leads to fibroblast activation and myofibroblast differentiation, which is mainly characterized by an overexpression of α-smooth muscle actin (α-SMA) and collagens. Although ET-1 is a potent profibrotic mediator, the signal transductions and subtype specificity of ETR contributing to cell proliferation, as well as α-SMA and collagen I synthesis in human cardiac fibroblasts are not well clarified. This study aimed to evaluate the subtype specificity and signal transduction of ETR on fibroblast activation and myofibroblast differentiation. Treatment with ET-1 induced fibroblast proliferation, and synthesis of myofibroblast markers, α-SMA, and collagen I through the ET_AR subtype. Inhibition of G_αq protein, not G_αi or G_βγ, inhibited these effects of ET-1, indicating the essential role of G_αq protein-mediated ET_AR signaling. In addition, ERK1/2 was required for ET_AR/G_αq axis-induced proliferative capacity and overexpression of these myofibroblast markers. Antagonism of ETR with ETR antagonists (ERAs), ambrisentan and bosentan, inhibited ET-1-induced cell proliferation and synthesis of α-SMA and collagen I. Furthermore, ambrisentan and bosentan promoted the reversal of myofibroblasts after day 3 of treatment, with loss of proliferative ability and a reduction in α-SMA synthesis, confirming the restorative effects of ERAs. This novel work reports on the ET_AR/G_αq/ERK signaling pathway for ET-1 actions and blockade of ETR signaling with ERAs, representing a promising therapeutic strategy for prevention and restoration of ET-1-induced cardiac fibrosis. Full article

(This article belongs to the Special Issue Cardiac Fibrosis: Molecular Pathology and Therapeutics)

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14 pages, 2448 KiB

Open AccessArticle

Biglycan Involvement in Heart Fibrosis: Modulation of Adenosine 2A Receptor Improves Damage in Immortalized Cardiac Fibroblasts

by Michele Scuruchi, Federica Mannino, Chiara Imbesi, Giovanni Pallio, Giovanna Vermiglio, Gianluca Bagnato, Letteria Minutoli, Alessandra Bitto, Francesco Squadrito and Natasha Irrera

Int. J. Mol. Sci. 2023, 24(2), 1784; https://doi.org/10.3390/ijms24021784 - 16 Jan 2023

Cited by 6 | Viewed by 1708

Abstract

Cardiac fibrosis is a common pathological feature of different cardiovascular diseases, characterized by the aberrant deposition of extracellular matrix (ECM) proteins in the cardiac interstitium, myofibroblast differentiation and increased fibrillar collagen deposition stimulated by transforming growth factor (TGF)-β activation. Biglycan (BGN), a small leucine-rich proteoglycan (SLRPG) integrated within the ECM, plays a key role in matrix assembly and the phenotypic control of cardiac fibroblasts. Moreover, BGN is critically involved in pathological cardiac remodeling through TGF-β binding, thus causing myofibroblast differentiation and proliferation. Adenosine receptors (ARs), and in particular A_2AR, may play a key role in stimulating fibrotic damage through collagen production/deposition, as a consequence of cyclic AMP (cAMP) and AKT activation. For this reason, A_2AR modulation could be a useful tool to manage cardiac fibrosis in order to reduce fibrotic scar deposition in heart tissue. Therefore, the aim of the present study was to investigate the possible crosstalk between A_2AR and BGN modulation in an in vitro model of TGF-β-induced fibrosis. Immortalized human cardiac fibroblasts (IM-HCF) were stimulated with TGF-β at the concentration of 10 ng/mL for 24 h to induce a fibrotic phenotype. After applying the TGF-β stimulus, cells were treated with two different A_2AR antagonists, Istradefylline and ZM241385, for an additional 24 h, at the concentration of 10 µM and 1 µM, respectively. Both A_2AR antagonists were able to regulate the oxidative stress induced by TGF-β through intracellular reactive oxygen species (ROS) reduction in IM-HCFs. Moreover, collagen1a1, MMPs 3/9, BGN, caspase-1 and IL-1β gene expression was markedly decreased following A_2AR antagonist treatment in TGF-β-challenged human fibroblasts. The results obtained for collagen1a1, SMAD3, α-SMA and BGN were also confirmed when protein expression was evaluated; phospho-Akt protein levels were also reduced following Istradefylline and ZM241385 use, thus suggesting that collagen production involves AKT recruited by the A_2AR. These results suggest that A_2AR modulation might be an effective therapeutic option to reduce the fibrotic processes involved in heart pathological remodeling. Full article

(This article belongs to the Special Issue Cardiac Fibrosis: Molecular Pathology and Therapeutics)

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12 pages, 5083 KiB

Open AccessArticle

The Novel AT2 Receptor Agonist β-Pro7-AngIII Exerts Cardiac and Renal Anti-Fibrotic and Anti-Inflammatory Effects in High Salt-Fed Mice

by Yan Wang, Jonathan Yodgee, Mark Del Borgo, Iresha Spizzo, Levi Nguyen, Marie-Isabel Aguilar, Kate M. Denton, Chrishan S. Samuel and Robert E. Widdop

Int. J. Mol. Sci. 2022, 23(22), 14039; https://doi.org/10.3390/ijms232214039 - 14 Nov 2022

Cited by 6 | Viewed by 1447

Abstract

A high salt (HS) diet is associated with an increased risk for cardiovascular diseases (CVDs) and fibrosis is a key contributor to the organ dysfunction involved in CVDs. The activation of the renin angiotensin type 2 receptor (AT₂R) has been considered as organ protective in many CVDs. However, there are limited AT₂R-selective agonists available. Our first reported β-substituted angiotensin III peptide, β-Pro⁷-AngIII, showed high selectivity for the AT₂R. In the current study, we examine the potential anti-fibrotic and anti-inflammatory effects of this novel AT₂R-selective peptide on HS-induced organ damage. FVB/N mice fed with a 5% HS diet for 8 weeks developed cardiac and renal fibrosis and inflammation, which were associated with increased TGF-β1 levels in heart, kidney and plasma. Four weeks’ treatment (from weeks 5–8) with β-Pro⁷-AngIII inhibited the HS-induced cardiac and renal fibrosis and inflammation. These protective effects were accompanied by reduced local and systemic TGF-β1 as well as reduced cardiac myofibroblast differentiation. Importantly, the anti-fibrotic and anti-inflammatory effects caused by β-Pro⁷-AngIII were attenuated by the AT₂R antagonist PD123319. These results demonstrate, for the first time, the cardio- and reno-protective roles of the AT₂R-selective β-Pro⁷-AngIII, highlighting it as an important therapeutic that can target the AT₂R to treat end-organ damage. Full article

(This article belongs to the Special Issue Cardiac Fibrosis: Molecular Pathology and Therapeutics)

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23 pages, 5830 KiB

Open AccessArticle

Storax Attenuates Cardiac Fibrosis following Acute Myocardial Infarction in Rats via Suppression of AT1R–Ankrd1–P53 Signaling Pathway

by Zhuo Xu, Danni Lu, Jianmei Yuan, Liying Wang, Jiajun Wang, Ziqin Lei, Si Liu, Junjie Wu, Jian Wang and Lihua Huang

Int. J. Mol. Sci. 2022, 23(21), 13161; https://doi.org/10.3390/ijms232113161 - 29 Oct 2022

Cited by 5 | Viewed by 1895

Abstract

Myocardial fibrosis following acute myocardial infarction (AMI) seriously affects the prognosis and survival rate of patients. This study explores the role and regulation mechanism of storax, a commonly used traditional Chinese medicine for treatment of cardiovascular diseases, on myocardial fibrosis and cardiac function. The AMI rat model was established by subcutaneous injection of Isoproterenol hydrochloride (ISO). Storax (0.1, 0.2, 0.4 g/kg) was administered by gavage once/d for 7 days. Electrocardiogram, echocardiography, hemodynamic and cardiac enzyme in AMI rats were measured. HE, Masson, immunofluorescence and TUNEL staining were used to observe the degree of pathological damage, fibrosis and cardiomyocyte apoptosis in myocardial tissue, respectively. Expression of AT1R, CARP and their downstream related apoptotic proteins were detected by WB. The results demonstrated that storax could significantly improve cardiac electrophysiology and function, decrease serum cardiac enzyme activity, reduce type I and III collagen contents to improve fibrosis and alleviate myocardial pathological damage and cardiomyocyte apoptosis. It also found that storax can significantly down-regulate expression of AT1R, Ankrd1, P53, P-p53 (ser 15), Bax and cleaved Caspase-3 and up-regulate expression of Mdm2 and Bcl-2. Taken together, these findings indicated that storax effectively protected cardiomyocytes against myocardial fibrosis and cardiac dysfunction by inhibiting the AT1R–Ankrd1–P53 signaling pathway. Full article

(This article belongs to the Special Issue Cardiac Fibrosis: Molecular Pathology and Therapeutics)

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Review

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22 pages, 1119 KiB

Open AccessReview

Signaling Pathways and Potential Therapeutic Strategies in Cardiac Fibrosis

by Alexandrine Bertaud, Ahmad Joshkon, Xavier Heim, Richard Bachelier, Nathalie Bardin, Aurélie S. Leroyer and Marcel Blot-Chabaud

Int. J. Mol. Sci. 2023, 24(2), 1756; https://doi.org/10.3390/ijms24021756 - 16 Jan 2023

Cited by 9 | Viewed by 3071

Abstract

Cardiac fibrosis constitutes irreversible necrosis of the heart muscle as a consequence of different acute (myocardial infarction) or chronic (diabetes, hypertension, …) diseases but also due to genetic alterations or aging. Currently, there is no curative treatment that is able to prevent or attenuate this phenomenon that leads to progressive cardiac dysfunction and life-threatening outcomes. This review summarizes the different targets identified and the new strategies proposed to fight cardiac fibrosis. Future directions, including the use of exosomes or nanoparticles, will also be discussed. Full article

(This article belongs to the Special Issue Cardiac Fibrosis: Molecular Pathology and Therapeutics)

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