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Background: Macrophages play a crucial role in the development of cardiac fibrosis (CF). Although our previous studies have shown that glycogen metabolism plays an important role in macrophage inflammatory phenotype, the role and mechanism of modifying macrophage phenotype by regulating glycogen metabolism and thereby improving CF have not been reported. Methods: Here, we took glycogen synthetase kinase 3β (GSK3β) as the target and used its inhibitor NaW to enhance macrophage glycogen metabolism, transform M2 phenotype into anti-fibrotic M1 phenotype, inhibit fibroblast activation into myofibroblasts, and ultimately achieve the purpose of CF treatment. Results: NaW increases the pH of macrophage lysosome through transmembrane protein 175 (TMEM175) and caused the release of Ca2+ through the lysosomal Ca2+ channel mucolipin-2 (Mcoln2). At the same time, the released Ca2+ activates TFEB, which promotes glucose uptake by M2 and further enhances glycogen metabolism. NaW transforms the M2 phenotype into the anti-fibrotic M1 phenotype, inhibits fibroblasts from activating myofibroblasts, and ultimately achieves the purpose of treating CF. Conclusion: Our data indicate the possibility of modifying macrophage phenotype by regulating macrophage glycogen metabolism, suggesting a potential macrophage-based immunotherapy against CF. [ABSTRACT FROM AUTHOR]

Heart diseases remain the primary cause of human mortality in the world. Although conventional therapeutic opportunities fail to halt or recover cardiac fibrosis, the promising clinical results and therapeutic efficacy of engineered chimeric antigen receptor (CAR) T cell therapy show several advancements. However, the current models of CAR‐T cells need further improvement since the T cells are associated with the triggering of excessive inflammatory cytokines that directly affect cardiac functions. Thus, the current study highlights the critical function of heart immune cells in tissue fibrosis and repair. The study also confirms CAR‐T cell as an emerging therapeutic for treating cardiac fibrosis, explores the current roadblocks to CAR‐T cell therapy, and considers future outlooks for research development. Significance statement: The necessity and importance of chimeric antigen receptor (CAR) T cells and their therapeutic efficiency in treating diseases other than cancer, mainly cardiovascular diseases, have emerged in recent years. However, there is still room for advancement in the current models of CAR‐T cell therapy. This paper highlights the evolution and roadblocks of CAR‐T technology at different levels, from technical concerns to clinical outcomes, in an attempt to improve the therapeutic efficiency of CAR‐T cell therapy in this area. [ABSTRACT FROM AUTHOR]

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The aim of the present study is to investigate the ameliorative potential of the aqueous extract of Indigofera tinctoria (IT) in aging-induced inflammation and its associated cardiac hypertrophy and fibrosis. Young (3-month-old) and aged (24–26-month-old) male Wistar albino rats were grouped into young control, aged control, aged + IT, and young + IT. The animals in the supplementary groups received 200 mg/kg BWT of aqueous extract of IT orally once a day for 21 days. Aged animals showed prolonged QT interval and increased weight and volume of the heart with a thickening ventricular wall. Infiltration of leukocytes and increased cardiomyocyte diameter and decreased numerical density along with cardiomyocyte apoptosis and increased collagen accumulation were also seen in aged myocardium when compared to the young. The expression profile of various pro-inflammatory cytokines such as IL-6, IL-1β, TNF-α, NFκB, and iNOS was increased with a concomitant reduction in IL-10 expression in the aged compared to the young. In addition, a marked increase in ROS generation, TGF-β, and α-SMA levels is evident in the aged myocardium. These pathological changes were greatly reversed in aged animals supplemented with IT. Furthermore, the aged + IT group showed repression of pro-inflammatory markers with a subsequent increase in IL-10 expression. Contrarily, no marked changes were observed between young and young + IT groups. Taken together, it is concluded that the aqueous extract of Indigofera tinctoria suppresses cardiac fibrosis and hypertrophy by repressing the inflammation and its associated activation of TGFβ and myofibroblast conversion. [ABSTRACT FROM AUTHOR]

The aim of the present study is to investigate the ameliorative potential of the aqueous extract of Indigofera tinctoria (IT) in aging-induced inflammation and its associated cardiac hypertrophy and fibrosis. Young (3-month-old) and aged (24–26-month-old) male Wistar albino rats were grouped into young control, aged control, aged + IT, and young + IT. The animals in the supplementary groups received 200 mg/kg BWT of aqueous extract of IT orally once a day for 21 days. Aged animals showed prolonged QT interval and increased weight and volume of the heart with a thickening ventricular wall. Infiltration of leukocytes and increased cardiomyocyte diameter and decreased numerical density along with cardiomyocyte apoptosis and increased collagen accumulation were also seen in aged myocardium when compared to the young. The expression profile of various pro-inflammatory cytokines such as IL-6, IL-1β, TNF-α, NFκB, and iNOS was increased with a concomitant reduction in IL-10 expression in the aged compared to the young. In addition, a marked increase in ROS generation, TGF-β, and α-SMA levels is evident in the aged myocardium. These pathological changes were greatly reversed in aged animals supplemented with IT. Furthermore, the aged + IT group showed repression of pro-inflammatory markers with a subsequent increase in IL-10 expression. Contrarily, no marked changes were observed between young and young + IT groups. Taken together, it is concluded that the aqueous extract of Indigofera tinctoria suppresses cardiac fibrosis and hypertrophy by repressing the inflammation and its associated activation of TGFβ and myofibroblast conversion. [ABSTRACT FROM AUTHOR]

Introduction: Thymoquinone (TQ) is one of the active ingredients in herbal plants such as Nigella sativa which has antioxidant and anti-inflammatory properties thus may inhibits cardiac fibrosis formation. This study aims to determine the effectiveness of Thymoquinone as a cardioprotective agent in suppressing the extent of fibrosis in Wistar rats induced with lipopolysaccharide (LPS). Methods: This post-test only control study used 30 Wistar rats which were divided into 5 groups: saline, LPS-induced cardiac fibrosis, LPS-induced cardiac fibrosis treated with TQ 10 mg/mL, LPS-induced cardiac fibrosis treated with TQ 20 mg/mL, and LPS-induced cardiac fibrosis treated with TQ 40 mg/mL. Serum IL-6, GSH, and cTnT levels were measured using ELISA, and Mason's trichrome staining was used to assess myocardial fibrosis. Results: The LPS10+TQ20 and LPS10+TQ40 groups exhibited significantly lower levels of IL-6 compared to the LPS10+TQ10 group (p < 0.05). GSH levels did not show a significant decrease in the TQ groups across different doses (p=0.771). The TQ-treated group demonstrated lower cTnT levels compared to the LPS-only group (p<0.05). Thymoquinone treatment resulted in reduced fibrosis area compared to the LPS10 group (p<0.05). Conclusions: TQ has a promising cardioprotective effect on the formation of cardiac fibrosis in Wistar rats induced with LPS. [ABSTRACT FROM AUTHOR]

Simple Summary: Fibrosis can affect almost every organ and represents an increasing cause of morbidity and mortality worldwide. Despite significant progress in our understanding of the pathobiology of fibrosis, there is still a lack of putative anti-fibrotic targets to be exploited in anti-fibrosis therapies or used as biomarkers of fibrosis progression. The discovery that HIPK2 can control molecular pathways involved in fibrosis has opened a new field of study in both pathophysiology and the treatment of fibrosis. Fibrosis is an unmet medical problem due to a lack of evident biomarkers to help develop efficient targeted therapies. Fibrosis can affect almost every organ and eventually induce organ failure. Homeodomain-interacting protein kinase 2 (HIPK2) is a protein kinase that controls several molecular pathways involved in cell death and development and it has been extensively studied, mainly in the cancer biology field. Recently, a role for HIPK2 has been highlighted in tissue fibrosis. Thus, HIPK2 regulates several pro-fibrotic pathways such as Wnt/β-catenin, TGF-β and Notch involved in renal, pulmonary, liver and cardiac fibrosis. These findings suggest a wider role for HIPK2 in tissue physiopathology and highlight HIPK2 as a promising target for therapeutic purposes in fibrosis. Here, we will summarize the recent studies showing the involvement of HIPK2 as a novel regulator of fibrosis. [ABSTRACT FROM AUTHOR]

Right ventricular (RV) pressure loading leads to RV and left ventricular (LV) dysfunction through RV hypertrophy, dilatation and fibrosis. Relief of RV pressure load improves RV function. However, the impact and mechanisms on biventricular reverse‐remodelling and function are only partially characterized. We evaluated the impact of RV pressure overload relief on biventricular remodelling and function in a rabbit model of reversible pulmonary artery banding (PAB). Rabbits were randomized to three groups: (1) Sham‐operated controls (n = 7); (2) PAB (NDef, n = 7); (3) PAB followed by band deflation (Def, n = 5). Sham and NDef animals were sacrificed at 6 weeks after PAB surgery. Def animals underwent PAB deflation at 6 weeks and sacrifice at 9 weeks. Biventricular geometry, function, haemodynamics, hypertrophy and fibrosis were compared between groups using echocardiography, magnetic resonance imaging, high‐fidelity pressure‐tipped catheters and histology. RV pressure loading caused RV dilatation, systolic dysfunction, myocyte hypertrophy and LV compression which improved after PAB deflation. RV end‐diastolic pressure (RVEDP) decreased after PAB deflation, although remaining elevated vs. Sham. LV end‐diastolic pressure (LVEDP) was unchanged following PAB deflation. RV and LV collagen volumes in the NDef and Def group were increased vs. Sham, whereas RV and LV collagen volumes were similar between NDef and Def groups. RV myocyte hypertrophy (r = 0.75, P < 0.001) but not collagen volume was related to RVEDP. LV myocyte hypertrophy (r = 0.58, P = 0.016) and collagen volume (r = 0.56, P = 0.031) correlated with LVEDP. In conclusion, relief of RV pressure overload improves RV and LV geometry, hypertrophy and function independent of fibrosis. The long‐term implications of persistent fibrosis and increased biventricular filling pressures, even after pressure load relief, need further study. Key points: Right ventricular (RV) pressure loading in a pulmonary artery banding rabbit model is associated with RV dilatation, left ventricular (LV) compression; biventricular myocyte hypertrophy, fibrosis and dysfunction.The mechanisms and impact of RV pressure load relief on biventricular remodelling and function has not been extensively studied.Relief of RV pressure overload improves biventricular geometry in conjunction with improved RV myocyte hypertrophy and function independent of reduced fibrosis.These findings raise questions as to the importance of fibrosis as a therapeutic target. [ABSTRACT FROM AUTHOR]

Fibrosis, characterized by an excessive accumulation of extracellular matrix, has long been seen as an adaptive process that contributes to tissue healing and regeneration. More recently, however, cardiac fibrosis has been shown to be a central element in many cardiovascular diseases (CVDs), contributing to the alteration of cardiac electrical and mechanical functions in a wide range of clinical settings. This paper aims to provide a comprehensive review of cardiac fibrosis, with a focus on the main pathophysiological pathways involved in its onset and progression, its role in various cardiovascular conditions, and on the potential of currently available and emerging therapeutic strategies to counteract the development and/or progression of fibrosis in CVDs. We also emphasize a number of questions that remain to be answered, and we identify hotspots for future research. [ABSTRACT FROM AUTHOR]

Plumula nelumbinis has great medicinal potential as a herbal tea and traditional drug in China. This study was aimed to evaluate the anticardiac fibrosis of the total alkaloids of P. nelumbinis (TAP). TAP at 50 mg/kg/day significantly ameliorated isoproterenol‐induced cardiac fibrosis in mice (p <.05). The circulating lipidomics study revealed that TAP improved the lipid metabolism dysfunction in cardiac fibrosis. Meanwhile, TAP suppressed the lipid accumulation, decreased MDA level (p <.01) in heart, and increased FFA level (p <.01). Furthermore, integrating lipidomics, chemical profiles and pharmacology network analysis found that AMPK and PI3K/Akt signaling pathways were the potential targeted pathway by TAP to regulate lipid metabolism dysfunction including glycerophospholipid metabolism. Above all, TAP provided a potential anticardiac fibrosis effect partly through regulation of lipid profiles. Practical applications: The total alkaloids of Plumula nelumbinis (TAP) suppressed ISO‐induced cardiac fibrosis in mice.Network pharmacology analysis and experiments revealed that TAP‐regulated AMPK and PI3K/Akt signaling pathway to improve lipid metabolism disorder in cardiac fibrosis.This study provides evidence to the therapeutic potential of TAP in the treatment of ISO‐induced cardiac fibrosis and could be a drug candidate for prevention and treatment of cardiac fibrosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Radiation exposure has been linked to non-cancer effects such as heart disease. This study aimed to investigate radiation-induced heart disease in mice where the radiation exposure was either administered to the whole body or only to the bottom third of the body (partial body). Radiation damage was found in the hearts of mice following both whole-body and partial-body exposure. MiRNAs released from directly irradiated skeletal muscle cells in vitro were shown to result in damaging effects in unirradiated ventricular cardiac cells. This study suggests that a partial-body exposure to radiation should be thought of as a systemic effect rather than only an effect on the exposed tissue. Recent reports have shown a link between radiation exposure and non-cancer diseases such as radiation-induced heart disease (RIHD). Radiation exposures are often inhomogeneous, and out-of-target effects have been studied in terms of cancer risk, but very few studies have been carried out for non-cancer diseases. Here, the role of miRNAs in the pathogenesis of RIHD was investigated. C57Bl/6J female mice were whole- (WBI) or partial-body-irradiated (PBI) with 2 Gy of X-rays or sham-irradiated (SI). In PBI exposure, the lower third of the mouse body was irradiated, while the upper two-thirds were shielded. From all groups, hearts were collected 15 days or 6 months post-irradiation. The MiRNome analysis at 15 days post-irradiation showed that miRNAs, belonging to the myomiR family, were highly differentially expressed in WBI and PBI mouse hearts compared with SI hearts. Raman spectral data collected 15 days and 6 months post-irradiation showed biochemical differences among SI, WBI and PBI mouse hearts. Fibrosis in WBI and PBI mouse hearts, indicated by the increased deposition of collagen and the overexpression of genes involved in myofibroblast activation, was found 6 months post-irradiation. Using an in vitro co-culture system, involving directly irradiated skeletal muscle and unirradiated ventricular cardiac human cells, we propose the role of miR-1/133a as mediators of the abscopal response, suggesting that miRNA-based strategies could be relevant for limiting tissue-dependent reactions in non-directly irradiated tissues. [ABSTRACT FROM AUTHOR]

The isoproterenol (ISO)-induced myocardial fibrosis is considered a reliable and repeatable experimental model characterized by a relatively low mortality rate. Although is well-known that ISO stimulates the β1 adrenergic receptors at the myocardial level, a high degree of heterogeneity emerges around the doses and duration of the treatment generating unclear results. Therefore, we propose to gain insights into the progression of ISO-induced myocardial fibrosis, in order to critically analyze and optimize the experimental model. Male Wistar rats (12–14-week-old) were submitted to subcutaneous injection of ISO, in particular, two doses were selected: the commonly used dose of 5 mg/kg and a lower dose of 1 mg/kg, administered for 3 and 6 days. Biochemical and histological examinations were conducted either immediately after the last administration or after a recovering period of 7 or 14 days from the initial administration. Noteworthy, from our investigation emerged that even the lower dose of ISO was able to induce the maximal biochemical and histological alterations, suggesting that lower doses should be considered to control the progression of the damage more precisely and to identify a prodromic phase in which intervention with pharmacological or nutraceutical tools can be effectively attempted. [ABSTRACT FROM AUTHOR]

Aims Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarction (MI). In response to MI, the heart undergoes ventricular remodelling that leads to fibrotic scar due to excessive deposition of extracellular matrix mostly produced by myofibroblasts. The structural and mechanical properties of the fibrotic scar are critical determinants of heart function. Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) are the key effectors of the Hippo signalling pathway and are crucial for cardiomyocyte proliferation during cardiac development and regeneration. However, their role in cardiac fibroblasts, regulating post-MI fibrotic and fibroinflammatory response, is not well established. Methods and results Using mouse model, we demonstrate that Yap/Taz are activated in cardiac fibroblasts after MI and fibroblasts-specific deletion of Yap/Taz using Col1a2Cre(ER)T mice reduces post-MI fibrotic and fibroinflammatory response and improves cardiac function. Consistently, Yap overexpression elevated post-MI fibrotic response. Gene expression profiling shows significant downregulation of several cytokines involved in post-MI cardiac remodelling. Furthermore, Yap/Taz directly regulate the promoter activity of pro-fibrotic cytokine interleukin-33 (IL33) in cardiac fibroblasts. Blocking of IL33 receptor ST2 using the neutralizing antibody abrogates the Yap-induced pro-fibrotic response in cardiac fibroblasts. We demonstrate that the altered fibroinflammatory programme not only affects the nature of cardiac fibroblasts but also the polarization as well as infiltration of macrophages in the infarcted hearts. Furthermore, we demonstrate that Yap/Taz act downstream of both Wnt and TGFβ signalling pathways in regulating cardiac fibroblasts activation and fibroinflammatory response. Conclusion We demonstrate that Yap/Taz play an important role in controlling MI-induced cardiac fibrosis by modulating fibroblasts proliferation, transdifferentiation into myofibroblasts, and fibroinflammatory programme. [ABSTRACT FROM AUTHOR]

The accumulation of fibrosis in cardiac tissues is one of the leading causes of heart failure. The principal cellular effectors in cardiac fibrosis are activated fibroblasts and myofibroblasts, which serve as the primary source of matrix proteins. TGF-β signaling pathways play a prominent role in cardiac fibrosis. The control of TGF-β by KLF5 in cardiac fibrosis has been demonstrated for modulating cardiovascular remodeling. Since the expression of KLF5 is reduced, the accumulation of fibrosis diminishes. Because the molecular mechanism of fibrosis is still being explored, there are currently few options for effectively reducing or reversing it. Studying metabolic alterations is considered an essential process that supports the explanation of fibrosis in a variety of organs and especially the glycolysis alteration in the heart. However, the interplay among the main factors involved in fibrosis pathogenesis, namely TGF-β, KLF5, and the metabolic process in glycolysis, is still indistinct. In this review, we explain what we know about cardiac fibroblasts and how they could help with heart repair. Moreover, we hypothesize and summarize the knowledge trend on the molecular mechanism of TGF-β, KLF5, the role of the glycolysis pathway in fibrosis, and present the future therapy of cardiac fibrosis. These studies may target therapies that could become important strategies for fibrosis reduction in the future. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis is a common pathological process of most cardiac diseases, which may result in cardiac function impairment. Long noncoding RNAs (lncRNAs) have been verified as crucial regulators of cardiac fibrosis. This study explored the function and molecular mechanism of PVT1 in cardiac fibrosis. TGF-β1-exposed human cardiac fibroblasts (HCF-a) and isoproterenol (ISO)-treated mice were used as the in vitro and in vivo cardiac fibrosis models. PVT1, miR-145, and HCN1 expression was determined by quantitative RT-PCR. Cell proliferation was evaluated by CCK-8 and EdU fluorescence staining. α-SMA and collagen I expression was assessed by immunohistochemical staining and immunofluorescence staining. Protein levels of fibrosis-related factors were assessed by Western blotting. The interaction between miR-145 and PVT1/HCN1 was evaluated by dual luciferase assay. ChIP assay was used to validate the binding of CREB1 to the promoter of PVT1. Cardiac fibrosis in mice was observed by H&E and Masson's trichrome staining. PVT1 and HCN1 were up-regulated, while miR-145 was down-regulated in the cardiac fibrosis models. PVT1 knockdown restrained TGF-β1-induced proliferation and activation of HCF-a cells. CREB1 bound to the promoter of PVT1 and activated its transcription. Mechanistically, PVT1 enhanced HCN1 expression via sponging miR-145. Finally, silencing of PVT1 attenuated cardiac fibrosis via regulating miR-145/HCN1 axis in mice in vivo. PVT1 contributed to cardiac fibrosis by increasing HCN1 expression via sponging miR-145, which suggested that targeting PVT1 may be a therapeutic option for cardiac fibrosis and cardiac diseases. • PVT1 and HCN1 are up-regulated, while miR-145 is down-regulated in cardiac fibrosis. • PVT1 drives TGF-β1-induced fibrogenesis in HCF-a cells. • CREB1 promotes the transcription of PVT1. • PVT1 promotes cardiac fibrosis via miR-145/HCN1 axis in vitro and in vivo. [ABSTRACT FROM AUTHOR]

• Cardiac fibrosis continues to play an important role in driving adverse clinical outcomes for a growing number of patients worldwide. • Various cellular and molecular pathways have been implicated in the pathogenesis of cardiac fibrosis. • Recent work has revealed that the local immune microenvironment may have a critical role underlying the progression of cardiac fibrosis. • Stem cell therapy for treating cardiac fibrosis has been fraught with challenges, but ongoing studies suggest a more precise approach may have benefits in blunting the progression of fibrotic processes in the heart. Cardiac fibrosis is a significant contributor to heart failure, a condition that continues to affect a growing number of patients worldwide. Various cardiovascular comorbidities can exacerbate cardiac fibrosis. While fibroblasts are believed to be the primary cell type underlying fibrosis, recent and emerging data suggest that other cell types can also potentiate or expedite fibrotic processes. Over the past few decades, clinicians have developed therapeutics that can blunt the development and progression of cardiac fibrosis. While these strategies have yielded positive results, overall clinical outcomes for patients suffering from heart failure continue to be dire. Herein, we overview the molecular and cellular mechanisms underlying cardiac tissue fibrosis. To do so, we establish the known mechanisms that drive fibrosis in the heart, outline the diagnostic tools available, and summarize the treatment options used in contemporary clinical practice. Finally, we underscore the critical role the immune microenvironment plays in the pathogenesis of cardiac fibrosis. [ABSTRACT FROM AUTHOR]

[Display omitted] Cardiac fibrosis is pivotal in the progression of numerous cardiovascular diseases. This phenomenon is hallmarked by an excessive deposition of ECM protein secreted by myofibroblasts, leading to increased myocardial stiffness. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that belongs to the proprotein-converting enzyme family. It has emerged as a viable therapeutic target for reducing plasma low-density lipoprotein cholesterol. However, the exact mechanism via which PCSK9 impacts cardiac fibrosis remains unclear. In the present research, an increase in circulating PCSK9 protein levels was observed in individuals with myocardial infarction and rat models of myocardial infarction. Moreover, the inhibition of circulating PCSK9 in rats was found to reduce post-infarction fibrosis. In vitro experiments further demonstrated that overexpression of PCSK9 or stimulation by extracellular PCSK9 recombinant protein enhanced the transformation of cardiac fibroblasts to myofibroblasts. This process also elevated collagen Ⅰ, and Ⅲ, as well as α-SMA protein levels. However, these effects were countered when co-incubated with the STAT3 inhibitor S3I-201. This study suggests that PCSK9 may function as a novel regulator of myocardial fibrosis, primarily via the JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) triggers adverse ventricular remodeling (VR), cardiac fibrosis, and subsequent heart failure. Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is postulated to play a significant role in VR processing via activation of the TLR4 inflammatory pathway. We hypothesized that an eNAMPT specific monoclonal antibody (mAb) could target and neutralize overexpressed eNAMPT post-MI and attenuate chronic cardiac inflammation and fibrosis. We investigated humanized ALT-100 and ALT-300 mAb with high eNAMPT-neutralizing capacity in an infarct rat model to test our hypothesis. ALT-300 was 99mTc-labeled to generate 99mTc-ALT-300 for imaging myocardial eNAMPT expression at 2 hours, 1 week, and 4 weeks post-IRI. The eNAMPT-neutralizing ALT-100 mAb (0.4 mg/kg) or saline was administered intraperitoneally at 1 hour and 24 hours post-reperfusion and twice a week for 4 weeks. Cardiac function changes were determined by echocardiography at 3 days and 4 weeks post-IRI. 99mTc-ALT-300 uptake was initially localized to the ischemic area at risk (IAR) of the left ventricle (LV) and subsequently extended to adjacent non-ischemic areas 2 hours to 4 weeks post-IRI. Radioactive uptake (%ID/g) of 99mTc-ALT-300 in the IAR increased from 1 week to 4 weeks (0.54 ± 0.16 vs. 0.78 ± 0.13, P < 0.01). Rats receiving ALT-100 mAb exhibited significantly improved myocardial histopathology and cardiac function at 4 weeks, with a significant reduction in the collagen volume fraction (%LV) compared to controls (21.5 ± 6.1% vs. 29.5 ± 9.9%, P < 0.05). Neutralization of the eNAMPT/TLR4 inflammatory cascade is a promising therapeutic strategy for MI by reducing chronic inflammation, fibrosis, and preserving cardiac function. [Display omitted] • Imaging of radiolabeled antibody reveals eNAMPT involving in ischemic injury. • Humanized eNAMPT-neutralizing mAb shows anti-fibrotic effects in infarcted hearts. • eNAMPT functions as a DAMP leading to post-infarct cardiac remodeling and heart failure. • eNAMPT/TLR4 inflammatory cascade drives post-infarct cardiac remodeling. • Anti-eNAMPT antibody theranostics provides diagnostic and therapeutic potential. [ABSTRACT FROM AUTHOR]

Fibrosis has been widely investigated in acute phase of myocardial infarction (MI). However, the mechanism of sustained fibrosis after MI hasn't been elucidated, which eventually gives rise to ventricular aneurysm (VA) formation chronic while lethal. Neutrophil as vital cell facilitating the fibrotic repair after acute MI may not project its effect to chronic phase unless neutrophil extracellular traps (NETs) were secreted and accumulating. The aim of this study was to investigate whether NETs contribute to the sustained fibrosis and VA formation after MI. We identified NETs in ventricular aneurysm of patients. Accordingly, NETs increased in peripheral blood of VA patients. Moreover, in rat VA NETs were also identified. Stimulated by NETs, the migration of fibroblast was enhanced and the differentiation of cardiac myofibroblast was initiated. Smad, MAPK and RhoA signaling pathways were activated by NETs incubation. And additional deposition with DNase I to disrupt NETs and abrogated NETs induced fibrosis both in vivo and vitro. These results collectively demonstrate a novel profibrotic role for NETs in chronic cardiac fibrosis and VA formation. • Identifying that NETs participate in the fibrosis after MI and lead to the formation of ventricular aneurysm. • Identifying that Ventricular aneurysm formed after MI follows the pattern of perivascular fibrosis expansion where NETs exist and crosslinked with thrombosis. • Describing that NETs could induce the differentiation from cardiac fibroblast to myofibroblast and upregulate collagen synthesis. • Employing Dnase I administration as disrupt the DNA skeleton of NETs to abrogate NETs induced fibrotic upregulation both in vivo and vitro. • Providing an accessible and replicable method for neutrophils isolation and NETs acquirement from rats. [ABSTRACT FROM AUTHOR]

Cardiomyopathy and fibrosis are the main causes of heart failure in diabetes patients. For therapeutic purposes, a delivery system is required to enhance antidiabetic drug efficacy and specifically target profibrotic pathways in cardiomyocytes. Nanoparticles (NPs) have distinct advantages, including biocompatibility, bioavailability, targeting efficiency, and minimal toxicity, which make them ideal for antidiabetic treatment. In this review, we overview the latest information on the pathogenesis of cardiomyopathy and fibrosis in diabetes patients. We summarize how NP applications improve insulin and liraglutide efficacy and their sustained release upon oral administration. We provide a comprehensive review of the results of NP clinical trials in diabetes patients and of animal studies investigating the effects of NP-mediated anti-fibrotic treatments. Collectively, the application of advanced NP delivery systems in the treatment of cardiomyopathy and fibrosis in diabetes patients is a promising and innovative therapeutic strategy. Conventional anti-diabetic regimens are challenged by the drug's efficacy, weak potency in the protection from cardiomyopathy and suppression of cardiac fibrosis progression. Nanoparticles hold distinguished advantaged such as biocompatibility, water solubility, bioavailability, target efficiency and minimized toxicity, all of which make them ideal for drug, nucleic acid and protein delivery in anti-diabetic treatment. For the therapeutic purposes, the desirable NPs delivery system should be safe with well-controlled drug retention and release and bioavailability. Lipid- and chemical- modified nanoparticles make it possible for oral administration of insulin and GLP-1 RAs in diabetic patients with sustained release and stable reduction of HbA1c. NPs are designed and desirable to deliver nucleic acids, small molecules or peptides specifically to the heart where they block TGF-β1 activation in fibroblasts and cell type transition from epithelial to fibroblasts, resulting in the inhibition of cardiac fibrosis progression. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Duchenne muscular dystrophy (DMD) leads to progressive cardiomyopathy. Detection of myocardial fibrosis with late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR) is critical for clinical management. Due to concerns of brain deposition of gadolinium, non-contrast methods for detecting and monitoring myocardial fibrosis would be beneficial. Objectives: We hypothesized that native T1 mapping and/or circumferential (εcc) and longitudinal (εls) strain can detect myocardial fibrosis. Methods: 156 CMRs with gadolinium were performed in 66 DMD boys and included: (1) left ventricular ejection fraction (LVEF), (2) LGE, (3) native T1 mapping and myocardial tagging (εcc-tag measured using harmonic phase analysis). LGE was graded as: (1) presence/absence by segment, slice, and globally; (2) global severity from 0 (no LGE) to 4 (severe); (3) percent LGE using full width half maximum (FWHM). εls and εcc measured using feature tracking. Regression models to predict LGE included native T1 and either εcc-tag or εls and εcc measured at each segment, slice, and globally. Results: Mean age and LVEF at first CMR were 14 years and 54%, respectively. Global εls and εcc strongly predicted presence or absence of LGE (OR 2.6 [1.1, 6.0], p = 0.029, and OR 2.3 [1.0, 5.1], p = 0.049, respectively) while global native T1 did not. Global εcc, εls, and native T1 predicted global severity score (OR 2.6 [1.4, 4.8], p = 0.002, OR 2.6 [1.4, 6.0], p = 0.002, and OR 1.8 [1.1, 3.1], p = 0.025, respectively). εls correlated with change in LGE by severity score (n = 33, 3.8 [1.0, 14.2], p = 0.048) and εcc-tag correlated with change in percent LGE by FWHM (n = 34, OR 0.2 [0.1, 0.9], p = 0.01). Conclusions: Pre-contrast sequences predict presence and severity of LGE, with εls and εcc being more predictive in most models, but there was not an observable advantage over using LVEF as a predictor. Change in LGE was predicted by εls (global severity score) and εcc-tag (FWHM). While statistically significant, our results suggest these sequences are currently not a replacement for LGE and may only have utility in a very limited subset of DMD patients. [ABSTRACT FROM AUTHOR]

Skeletal muscle consists of heterogeneous cell populations that work in concert to support musculoskeletal homeostasis and regeneration in the context of acute injury and chronic disease. In this past decade, the recently discovered sub-population of muscle resident stem cells known as fibro-adipogenic progenitors (FAPs) have been implicated in the pathogenesis and regenerative response to a number of musculoskeletal conditions ranging from acute muscle injury to neurodegenerative disease, muscular dystrophy, rotator cuff tears, sarcopenia and heterotopic ossification. The purpose of this literature review is to synthesize a complete collection of basic, translational, and clinical science evidence implicating FAPs in the pathogenesis and regenerative response to acute and chronic musculoskeletal diseases. This study is an extensive literature review of papers recently published on FAPs in the development of acute and chronic musculoskeletal degeneration, and their potential role in therapeutic regeneration of these injuries. In this review, we highlight the multipotency of FAPs on a molecular level and review their role in the pathogenesis of acute, chronic, and degenerative musculoskeletal disorders with implications for the development of future novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: Myocardial infarction (MI) induces an intense injury response that ultimately generates a collagen-dominated scar. Although required to prevent ventricular rupture, the fibrotic process is often sustained in a manner detrimental to optimal recovery. Cardiac myofibroblasts are the cells tasked with depositing and remodeling collagen and are a prime target to limit the fibrotic process after MI. Serotonin 2B receptor (5-HT2B) signaling has been shown to be harmful in a variety of cardiopulmonary pathologies and could play an important role in mediating scar formation after MI.Methods: We used 2 pharmacological antagonists to explore the effect of 5-HT2B inhibition on outcomes after MI and characterized the histological and microstructural changes involved in tissue remodeling. Inducible 5-HT2B ablation driven by Tcf21MCM and PostnMCM was used to evaluate resident cardiac fibroblast- and myofibroblast-specific contributions of 5-HT2B, respectively. RNA sequencing was used to motivate subsequent in vitro analyses to explore cardiac fibroblast phenotype.Results: 5-HT2B antagonism preserved cardiac structure and function by facilitating a less fibrotic scar, indicated by decreased scar thickness and decreased border zone area. 5-HT2B antagonism resulted in collagen fiber redistribution to thinner collagen fibers that were more anisotropic, enhancing left ventricular contractility, whereas fibrotic tissue stiffness was decreased, limiting the hypertrophic response of uninjured cardiomyocytes. Using a tamoxifen-inducible Cre, we ablated 5-HT2B from Tcf21-lineage resident cardiac fibroblasts and saw similar improvements to the pharmacological approach. Tamoxifen-inducible Cre-mediated ablation of 5-HT2B after onset of injury in Postn-lineage myofibroblasts also improved cardiac outcomes. RNA sequencing and subsequent in vitro analyses corroborate a decrease in fibroblast proliferation, migration, and remodeling capabilities through alterations in Dnajb4 expression and Src phosphorylation.Conclusions: Together, our findings illustrate that 5-HT2B expression in either cardiac fibroblasts or activated myofibroblasts directly contributes to excessive scar formation, resulting in adverse remodeling and impaired cardiac function after MI. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis is a hallmark of cardiac remodeling associated with nearly all forms of heart disease. Clinically, no effective therapeutic drugs aim to inhibit cardiac fibrosis, owing to the complex etiological heterogeneity and pathogenesis of this disease. A two-in-one protein structure, a ubiquitous expression profile and unique biophysical characteristics enable the involvement of transient receptor potential melastatin-subfamily member 7 (TRPM7) in the pathogenesis and development of fibrosis-related cardiac diseases, such as heart failure (HF), cardiomyopathies, arrhythmia and hyperaldosteronism. In response to a variety of stimuli, multiple bioactive molecules can activate TRPM7 and related signaling pathways, leading to fibroblast proliferation, differentiation and extracellular matrix production in cardiac fibroblasts. TRPM7-mediated Ca2+ signaling and TGF-β1 signaling pathways are critical for the formation of fibrosis. Accumulating evidence has demonstrated that TRPM7 is a potential pharmacological target for halting the development of fibrotic cardiac diseases. Reliable drug-like molecules for further development of high-affinity in vivo drugs targeting TRPM7 are urgently needed. The present review discusses the widespread and significant role of TRPM7 in cardiac fibrosis and focuses on its potential as a therapeutic target for alleviating heart fibrogenesis. [ABSTRACT FROM AUTHOR]

Age-related myocardial dysfunction is a very large healthcare burden. Here, we aimed to investigate whether ginsenoside Rb1 (Rb1) improves age-related myocardial dysfunction and to identify the relevant molecular mechanism. Young mice and aged mice were injected with Rb1 or vehicle for 3 months. Then, their cardiac function was inspected by transthoracic echocardiography. Serum and myocardium tissue were collected from all mice for histological or molecular expression analyses, including aging-related proteins, markers relevant to fibrosis and inflammation, and markers indicating the activation of the nuclear factor-kappa B (NF- κ B) pathway. Compared with the control condition, Rb1 treatment significantly increased the ejection fraction percentage and significantly decreased the internal diameter and volume of the left ventricle at the end-systolic and end-diastolic phases in aged mice. Rb1 treatment reduced collagen deposition and collagen I, collagen III, and transforming growth factor- β 1 protein expression levels in aged hearts. Rb1 also decreased the aging-induced myocardial inflammatory response, as measured by serum or myocardial interleukin-6 and tumor necrosis factor- α levels. Furthermore, Rb1 treatment in aged mice increased cytoplasmic NF- κ B but decreased nuclear NF- κ B, which indicated the suppression of the NF- κ B signaling pathway by regulating the translocation of NF- κ B. Rb1 could alleviate aging-related myocardial dysfunction by suppressing fibrosis and inflammation, which is potentially associated with regulation of the NF- κ B signaling pathway. [ABSTRACT FROM AUTHOR]

Ischaemic heart disease is one of the leading causes of death. Protease-activated receptor 2 (PAR2) is widely expressed within the cardiovascular system and is known to mediate inflammatory processes in various immunocytes, such as macrophages, mastocytes and neutrophils. Here, we investigated whether activating macrophage PAR2 modulates cardiac remodelling in a murine model of myocardial infarction. Myocardial infarction was produced by the permanent ligation of the left anterior descending coronary artery (LAD) in C57BL/6J background wild-type (WT) mice transplanted with bone marrow from WT or PAR2 knockout (PAR2 KO) mice. Hematopoietic deficiency of PAR2 had improvement of left ventricular systolic dysfunction and dilatation and decreased fibrosis deposition in remote zone at 1 week after LAD ligation. Inactivation of PAR2 also led to less recruitment of macrophages in myocardium, which was accompanied by decreased expression of pro-inflammatory cytokines. Furthermore, cultured cardiac fibroblasts (CFs) were activated and showed a fibrotic phenotype after being co-cultured in medium containing PAR2-activating macrophage, which enhances interferon-beta (INF-β) expression. The beneficial effects of macrophages with INF-β neutralisation or PAR2-deletion ameliorates the JAK/STAT3 pathway in CFs, which might be attributed to CF activation. These data suggest that macrophage-derived IFN-β plays a crucial role in adverse cardiac remodelling after myocardial infarction, at least in part, through a PAR2-dependent mechanism. • PAR2 deficiency in macrophage improves cardiac dysfunction in mice after MI. • PAR2 deficiency suppresses macrophage recruitment and inflammatory response in the post-MI hearts. • IFN-β mediates PAR2-related cardiac fibroblast activation through the JAK/STAT3 pathway. [ABSTRACT FROM AUTHOR]

The dysregulation of Long noncoding RNAs (lncRNAs) has been implicated in many cardiovascular diseases, including cardiac fibrosis. However, the functions and mechanisms of lncRNAs in cardiac fibroblasts (CFs) have not been fully elucidated. First, we observed a correlation between cardiac remodeling (CR) and lncRNA FAF (FGF9-associated factor, termed FAF) expression in the heart. In vitro, we found that the expression of lncRNA FAF was altered in CFs, whereas it behaved inconsistently in cardiomyocytes (CMs). Next, we investigated the effects of lncRNA FAF on angiotensinogen II (Ang II)-induced cardiac fibrosis in neonatal rat CFs and explored the mechanism underlying these effects. In this study, lncRNA FAF was enriched in CFs and was associated with cardiac fibrosis. Upregulation of lncRNA FAF significantly restrained Ang II-induced increases in cell proliferation, differentiation and collagen accumulation of CFs. Moreover, we found that the function of lncRNA FAF was mainly realized through Transforming growth factor β1 (TGFβ1) secretion and then downregulated phosphorylation of Smad2/3. Additional analysis revealed that Fibroblast growth factor 9 (FGF9) is a direct target of lncRNA FAF, as the overexpression of lncRNA FAF could increase the expression of FGF9 and knockdown of the FGF9 expression could attenuate the down-regulation of lncRNA FAF on TGFβ1-P-Smad2/3 pathway. Furthermore, knockdown of the FGF9 expression also abolished the inhibitory effect of FAF on fibrosis. In summary, we demonstrated that the overexpression of lncRNA FAF could inhibit fibrosis induced by Ang II via the TGFβ1-P-Smad2/3 signalling by targeting FGF9 in CFs. • LncRNA FAF is Associated with CR and Enriched in CFs. • LncRNA FAF Suppresses Fibrosis Induced by Ang II in CFs. • LncRNA FAF Regulates Fibrosis by Influencing the TGFβ1-P-Smad2/3 Signalling Pathway. • FGF9 Is the Target of LncRNA FAF. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis after myocardial infarction (MI) is mainly associated with cardiac fibroblasts and its differentiation is the key pathological process. However, the cellular mechanism of fibroblast-to-myofibroblast conversion has not been clarified and a deeper mechanistic understanding is needed. We found that miR-574–5p was up-regulated in TGF-β-induced myofibroblast differentiation. Silencing transiently miR-574–5p in HCFs, we found that suppression of miR-574–5p decreased myofibroblasts differentiation as validated by expression levels of fibrosis related genes, EDU imaging assay, wound healing assay and transwell assays. Conversely, overexpression of miR-574–5p displayed opposite results. ARID3A was verified as a direct target gene of miR-574–5p and decreased level of ARID3A forced fibroblast-to-myofibroblast differentiation of TGF-β-induced HCFs. Our data suggests that miR-574–5p plays a pivotal role in human cardiac fibroblasts (HCFs) myofibroblast differentiation and demonstrates that miR-574–5p and arid3a may be a novel therapeutic target for cardiac fibrosis. • We first demonstrated that miR-574–5p promotes the differentiation of HCFs. • ARID3A is the direct target gene of miR-574–5p. • Suppression of ARID3A recovered the anti-fibrotic response of miR-574–5p knockdown on TGF-β stimulation. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis is a common pathological change of many cardiovascular diseases. β-catenin has been shown to promote fibrosis. However, the precise role of its homolog γ-catenin in the process of fibrosis remains largely unclear. In this study, we found that the expression of γ-catenin was significantly decreased in angiotensin II (Ang II)-induced cardiac fibrosis model, contrary to most reports of β-catenin. Overexpression of γ-catenin in cardiac fibroblasts (CFs) significantly inhibited the expression of α-smooth muscle actin (α-SMA), whereas knocking down the expression of γ-catenin with siRNA promoted the occurrence of cardiac fibrosis. Mechanistically, γ-catenin could bind to GSK-3β to inhibit the phosphorylation of GSK-3β, therefore preventing cardiac fibrosis. Our study shows that γ-catenin is an important protective factor in cardiac fibrosis, which provides a new potential target for the treatment of cardiac fibrosis. [ABSTRACT FROM AUTHOR]

Background: The objectives of the study were to characterize and quantify cellular inflammation and structural remodeling of human atria and correlate findings with molecular markers of inflammation and patient surrogate outcome.Methods: Voluntary participants undergoing heart surgery were enrolled in the study and blood samples were collected prior to surgery, and right atrium samples were harvested intraoperatively. Blood samples were analyzed by flow cytometry and complete blood counts. Atrial samples were divided for fixed fibrosis analysis, homogenized for cytokine analysis and digested for single cell suspension flow cytometry.Results: A total of 18 patients were enrolled and samples assessed. Isolated cells from the atria revealed a CD45+ population of ~ 20%, confirming a large number of leukocytes. Further characterization revealed this population as 57% lymphocytes and 26% monocyte/macrophages (MoΦ), with the majority of the latter cells being classical (CD14++/CD16-). Interstitial fibrosis was present in 87% of samples and correlated significantly with patient age. Older patients (> 65) had significantly more atrial fibrosis and cellular inflammation. AFib patients had no distinguishing feature of atrial fibrosis and had significantly greater CD45+ MoΦ, increased expression of MMP9 and presented with a significant correlation in length of stay to CCL-2/MCP-1 and NLR (neutrophil-to-lymphocyte ratio).Conclusion: Atrial fibrosis is correlated with age and not determinate to AFib. However, severity of atrial leukocyte infiltration and markers of matrix degradation are determinant to AFib. This also correlated with CCL2 (or MCP-1) and NLR-indicative of marked inflammation. These data show the potential importance of diagnostic and prognostic assessments that could inform clinical decision making in regard to the intensity of AFib patient management. [ABSTRACT FROM AUTHOR]

MicroRNA-663 (miRNA-663) regulates the expression of transforming growth factor β1 (TGF-β1), which participates in the pathogenesis of myocardial fibrosis. Therefore, microRNA-663 may also serve a role in myocardial fibrosis. The present study aimed to determine whether miRNA-663 participates in myocardial fibrosis via interaction with TGF-β1. In the present study, the expression of miRNA-663 was significantly downregulated, whereas that of TGF-β1 was significantly upregulated in the endomyocardial biopsies of patients with myocardial fibrosis compared with those in control necropsies. Pearson's correlation analysis revealed that the expression levels of miRNA-663 were negatively correlated with those of TGF-β1 in patients with myocardial fibrosis, but not in the controls. Receiver operating characteristic curve analysis demonstrated that the downregulation of miRNA-663 distinguished patients with myocardial fibrosis from controls. In the AC16 human cardiomyocyte cell line, miRNA-663 overexpression resulted in downregulated TGF-β1 expression, whereas exogenous TGF-β1 treatment exhibited no significant effects on miRNA-663 expression. These results indicate that miRNA-663 may participate in myocardial fibrosis, possibly through interaction with TGF-β1. [ABSTRACT FROM AUTHOR]

Cancer patients receiving anthracycline-based chemotherapy (Anth-bC) may experience early cardiac fibrosis, which could be an important contributing mechanism to the development of impaired left ventricular (LV) function. Substance P, a neuropeptide that predominantly acts via the neurokinin 1 receptor (NK-1R), contributes to adverse myocardial remodelling and fibrosis in other cardiomyopathies. We sought to determine if NK-1R blockade is effective against doxorubicin (Dox – a frequently used Anth-bC)-induced cardiac fibrosis and cardiomyocyte apoptosis. In addition, we explored the direct effects of Dox on cardiac fibroblasts. Male Sprague-Dawley rats were randomised to receive saline, six cycles of Dox (1.5 mg Dox/kg/cycle) or Dox with an NK-1R antagonist (L732138, 5 mg/kg/daily through Dox treatment). At 8 weeks after the initial dose of Dox, LV function and histopathological myocardial fibrosis and cell apoptosis were assessed. Collagen secretion was measured in vitro to test direct Dox activation of cardiac fibroblasts. Rats undergoing Dox treatment (9 mg/kg cumulative dose) developed cardiac fibrosis and cardiomyocyte apoptosis. NK-1R blockade partially mitigated cardiac fibrosis while completely preventing cardiomyocyte apoptosis. This resulted in improved diastolic function. Furthermore, we found that Dox had direct effects on cardiac fibroblasts to cause increased collagen production and enhanced cell survival. This study demonstrates that cardiac fibrosis induced by Anth-bC can be reduced by NK-1R blockade. The residual fibrotic response is likely due to direct Dox effects on cardiac fibroblasts to produce collagen. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is one of the most dangerous cardiovascular events. Cardiac fibrosis is a common pathological feature of remodeling after injury that is related to adverse clinical results with no effective treatment. Previous studies have confirmed that TRIM44, an E3 ligase, can promote the proliferation and migration of various tumor cells. However, the role of TRIM44 in cardiac fibrosis remains unknown. Models of TGF-β1 stimulation and MI-induced fibrosis were established to investigate the role and potential underlying mechanism of TRIM44 in cardiac fibrosis. The results showed that cardiac fibrosis was significantly inhibited after TRIM44 knockdown in a mouse model of MI, while it was enhanced when TRIM44 was overexpressed. Furthermore, in vitro studies showed that fibrosis markers were significantly reduced in cardiac fibroblasts (CFs) with TRIM44 knockdown, whereas TRIM44 overexpression promoted the expression of fibrosis markers. Mechanistically, TRIM44 maintains TAK1 stability by inhibiting the degradation of k48-linked polyubiquitination-mediated ubiquitination, thereby increasing phosphorylated TAK1 expression in the fibrotic environment and activating MAPKs to promote fibrosis. Pharmacological inhibition of TAK1 phosphorylation reversed the fibrogenic effects of TRIM44 overexpression. Combined, these results suggest that TRIM44 is a potential therapeutic target for cardiac fibrosis. [Display omitted] • TRIM44 increased in myocardial tissue post-myocardial infarction. • Increased expression of TRIM44 can promote the progression of cardiac fibrosis post-myocardial infarction. • TRIM44 is involved in the regulation of fibrosis by stabilizing the expression of TAK1. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis has been known to play an important role in the etiology of heart failure after myocardial infarction (MI). B lymphoma Mo-MLV insertion region 1 homolog (BMI1), a transcriptional repressor, is important for fibrogenesis in the kidneys. However, the effect of BMI1 on ischemia-induced cardiac fibrosis remains unclear. BMI1 was strongly expressed in the infarct region 1 wk post-MI in mice and was detected by Western blot and histological analyses. Lentivirusmediated overexpression of BMI1 significantly promoted cardiac fibrosis, worsened cardiac function 4 wk after the intervention in vivo, and enhanced the proliferation and migration capabilities of fibroblasts in vitro, whereas downregulation of BMI1 decreased cardiac fibrosis and prevented cardiac dysfunction in mice 4 wk post-MI in vivo. Furthermore, upregulated BMI1 inhibited phosphatase and tensin homolog (PTEN) expression, enhanced phosphatidylinositol 3-kinase (PI3K) expression, and increased the phosphorylation level of Akt and mammalian target of rapamycin (mTOR) in mice 4 wk after lentiviral infection, which was in accordance with the changes seen in their infarcted myocardial tissues. At the same time, the effects of BMI1 on cardiac fibroblasts were reversed in vitro when these cells were exposed to NVP-BEZ235, a dual-kinase (PI3K/mTOR) inhibitor. In conclusion, BMI1 is associated with cardiac fibrosis and dysfunction after MI by regulating cardiac fibroblast proliferation and migration, and these effects could be partially explained by the regulation of the PTEN-PI3K/Akt-mTOR pathway. [ABSTRACT FROM AUTHOR]

Background: Chronic drinking leads to myocardial contractile dysfunction and dilated cardiomyopathy, and cardiac fibrosis is a consequence of these alcoholic injuries. Soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) to less bioactive diols, and EETs have cardioprotective properties. However, the effects of sEH inhibition in ethanol (EtOH)‐induced cardiac fibrosis are unknown. Methods: This study was designed to investigate the role and underlying mechanisms of sEH inhibition in chronic EtOH feeding‐induced cardiac fibrosis. C57BL/6J mice were fed a 4% Lieber‐DeCarli EtOH diet for 8 weeks, and the sEH inhibitor 1‐trifluoromethoxyphenyl‐3‐(1‐propionylpiperidin‐4‐yl) urea (TPPU) was administered throughout the experimental period. Results: The results showed that chronic EtOH intake led to cardiac dilatation, collagen deposition, and autophagosome accumulation, while TPPU administration ameliorated these effects. In vitro, treating primary cardiac fibroblasts (CFs) with EtOH resulted in CF activation, including alpha smooth muscle actin overexpression, collagen synthesis, and cell migration. Moreover, EtOH disturbed CF autophagic flux, as evidenced by the increased LC3 II/I ratio and SQSTM1 expression, and by the enhanced autophagosome accumulation. TPPU treatment prevented the activation of CF induced by EtOH and restored the impaired autophagic flux by suppressing mTOR activation. Conclusions: Taken together, these findings suggest that sEH pharmacological inhibition may be a unique therapeutic strategy for treating EtOH‐induced cardiac fibrosis. [ABSTRACT FROM AUTHOR]

Background/Aims: Apoptosis, fibrosis and NLRP3 inflammasome activation are involved in the development of diabetic cardiomyopathy (DCM). Human recombinant relaxin-3 (H3 relaxin) is a novel bioactive peptide that inhibits cardiac injury; however, whether H3 relaxin prevents cardiac injury in rats with DCM and the underlying mechanisms are unknown. Methods: To investigate the effect of H3 relaxin on DCM, we performed a study using H3 relaxin treatment in male Sprague-Dawley (SD) rats with streptozotocin (STZ)-induced diabetes (DM). We measured apoptosis, fibrosis and NLRP3 inflammasome markers in the rat hearts four and eight weeks after the rats were injected with STZ (65 mg/kg) by western blot analysis. Subsequently, 2 or 6 weeks after the STZ treatment, the rats were treated with H3 relaxin [2 µg/kg/d (A group) or 0.2 µg/kg/d (B group)] for 2 weeks. Cardiac function was evaluated by echocardiography to determine the extent of myocardial injury in the DM rats. The protein levels of apoptosis, fibrosis and NLRP3 inflammasome markers were used to assess myocardial injury. In addition, we determined the plasma levels of IL-1ß and IL-18 using a Milliplex MAP Rat Cytokine/Chemokine Magnetic Bead Panel kit. Results: The protein expression of cleaved caspase-8, caspase-9 and caspase-3 as well as fibrosis markers increased at 4 and 8 weeks in the STZ-induced diabetic hearts compared with the levels in the control group. Furthermore, the NLRP3 inflammasome was substantially activated in STZ-induced diabetic hearts, leading to increased IL-1ß and IL-18 levels. Compared with the DM group, the A group exhibited substantially better cardiac function. The protein levels of apoptosis markers were attenuated by H3 relaxin, indicating that H3 relaxin inhibited myocardial apoptosis in the hearts of diabetic rats. The protein expression of fibrosis markers was inhibited by H3 relaxin. Additionally, the protein expression and activation of the NLRP3 inflammasome were also effectively attenuated by H3 relaxin. Conclusions: This study is the first to demonstrate that H3 relaxin plays an antiapoptotic, anti-fibrotic and anti-inflammatory role in DCM. [ABSTRACT FROM AUTHOR]

The proliferation and differentiation of cardiac fibroblasts (CFs) is central to cardiac fibrosis. Betulinic acid (BA) is an active compound isolated from the bark of the birch tree Betula spp. (Betulaceae) and has been shown to attenuate hepatic fibrosis. However, the effect of BA on the high glucose‑induced fibrosis response in CFs remains to be elucidated, therefore, the present study investigated the effect of BA on high glucose‑induced CFs and examined the possible mechanism underlying the effect of BA on CF transdifferentiation. CFs were pre‑incubated with various concentrations of BA for 24 h and then stimulated with high glucose (25 mM) for various times. Cell proliferation was evaluated using an MTT assay. The mRNA expression levels of α‑smooth muscle actin (SMA) and transforming growth factor (TGF)‑β1 were determined using reverse transcription‑quantitative polymerase chain reaction analysis. The protein expression levels of α‑SMA, collagen I, collagen III, fibronectin, TGF‑β1, small mothers against decapentaplegic (Smad)2/3, phosphorylated (p)‑Smad2 and p‑Smad3 and were detected using western blot analysis. The data revealed that BA attenuated the CF proliferation and myofibroblast differentiation induced by high glucose. In addition, BA inhibited the expression of extracellular matrix (ECM) in the CFs induced by high glucose. It was also found that BA inhibited the high glucose‑induced phosphorylation of Smad2/3 in the CFs. Taken together, BA suppressed the high glucose‑induced increase in the proliferation of CFs and expression of ECM via inhibition of the TGF‑β1/Smad signaling pathway. Thus, BA may offer therapeutic potential towards the treatment of cardiac fibrosis. [ABSTRACT FROM AUTHOR]

Fusaric acid (FA) is a novel compound derived from a class of nicotinic acid derivatives, exhibiting activity against cancers. However, its role in regulating cardiac injury is limited. Our study was aimed to investigate the role and the underlying molecular mechanism of FA in heart fibrosis and hypertrophy. Isoproterenol (ISP) was used to induce cardiac fibrosis and hypertrophy in vitro and in vivo. FA administration ameliorated hypertrophy by reducing atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β −myosin heavy chain (β-MHC) in vitro and in vivo. Additionally, FA reduced collagen accumulation and fibrosis-related signals, including α- smooth muscle actin (α-SMA), Collagen type I and Collagen type III. Transforming growth factor-β1 (TGF-β1)/SMADs and mitogen-activated protein kinases (MAPKs), including p38, extracellular signal regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), signalling pathways were highly activated for ISP induction, which were prevented due to FA administration. Further, FA suppressed ISP-induced PI3K/AKT activity in a dose dependent manner. Of note, FA-reduced MAPKs phosphorylation was associated with phosphoinositide 3-Kinase (PI3K)/Protein kinase B (AKT) activity caused by ISP. However, PI3K/AKT activation showed no effects on TGF-β1/SMADs expression in FA-treated cells after ISP exposure. Together, FA might be an effective candidate agent for preventing cardiac fibrosis by modulating TGF-β1/SMADs and PI3K/AKT signalling pathways. [ABSTRACT FROM AUTHOR]

Fibrosis is present in an important proportion of myocardial disorders. Injury activates cardiac fibroblasts, which deposit excess extracellular matrix, increasing tissue stiffness, impairing cardiac function, and leading to heart failure. Clinical therapies that directly target excessive fibrosis are limited, and more effective treatments are needed. Immunotherapy based on chimeric antigen receptor (CAR) T cells is a novel technique that redirects T lymphocytes toward specific antigens to eliminate the target cells. It is currently used in haematological cancers but has demonstrated efficacy in mouse models of hypertensive cardiac fibrosis, with activated fibroblasts as the target cells. CAR T cell therapy is associated with significant toxicities, but CAR natural killer cells can overcome efficacy and safety limitations. The use of CAR immunotherapy offers a potential alternative to current therapies for fibrosis reduction and restoration of cardiac function in patients with myocardial fibrosis. [Display omitted] • New therapeutic approaches are needed to treat cardiac fibrosis. • CAR T cell immunotherapy has antifibrotic effect in cardiac fibrosis mouse models. • CAR NK cells could be an "off-the-shelf" therapy that avoids CAR T cell toxicity. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is a major form of heart disease that leads to immediate cardiomyocyte death due to ischemia and eventually fibrosis and scar formation and further dysfunction of myocardium and heart failure. Extracellular matrix (ECM) production and tissue repair is conducted by myofibroblasts, which are formed from the normal quiescent cardiac fibroblasts following transformational changes, through the active participation of transforming growth factor β (TGFβ) and its signaling pathways. TGFβ appears to be a 'Master of all trades', with respect to cardiac fibrosis, as it can promote cardiomyocyte apoptosis and cardiac hypertrophy. TGFβ signaling involves its binding to TGFβ receptor type II (TGFβRII), which recruits TGFβ receptor type I (TGFβRI), which are also known as activin receptor-like kinase (ALK) in five different isoforms. In canonical signaling pathways, ALK5 activates Smads 2 and 3, and ALK1 activates Smads 1 and 5. These pairs of Smads form a corresponding complex and then bind to Smad 4, to translocate into the nucleus, where transcriptional reprogramming is carried out to promote myofibroblast formation and ECM production, eventually leading to cardiac fibrosis. TGFβ levels are elevated in MI, thereby aggravating the myocardial injury further. Several microRNAs are involved in the regulation of TGFβ signaling at different steps, affecting different components. Therapeutic targeting of TGFβ signaling at ALK1-5 receptor activity level has met with limited success and extensive research is needed to develop therapies based on the components of TGFβ signaling pathway, for instance cardiac dysfunction and heart failure. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis is a common phenomenon in different types of heart diseases, such as ischemic heart disease, inherited cardiomyopathy mutations, diabetes, and ageing and is associated with morbidity and mortality. Increased accumulation of extracellular matrix (ECM) that impacts cardiac function, is the underlying cause of fibrotic heart disease. There are four different types of cardiac fibrosis, including, reactive interstitial fibrosis, replacement fibrosis, infiltrative interstitial fibrosis and endomyocardial fibrosis. They are involved in the activation and transformation of cardiac fibroblasts to myofibroblasts, which participate in ECM production and fibrotic process and several inflammatory pathways. Besides the ECM proteins, myofibroblasts also express smooth muscle α-actin, SM22 and caldesmon and other markers related to fibrotic process. Most commonly employed techniques to assess myocardial fibrosis include stress echocardiography, cardiac magnetic resonance imaging and positron emission tomography. Because of the involvement of renin-angiotensin-II-aldosterone system, transforming growth factor-ß signaling and activin-linked kinase 5 in the mechanisms of cardiac fibrosis, these pathways and the involved proteins are useful as therapeutic targets. However, because of the importance of these pathways in many other physiological functions, their therapeutic targeting needs to be approached with caution. [ABSTRACT FROM AUTHOR]

Background Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic necrotizing vasculitis characterized by hypereosinophilia. EGPA typically develops in three clinical phases, beginning with asthma, followed by tissue eosinophilia and finally systemic vasculitis. Cardiac involvement is the most important predictor of mortality; it occurs in approximately 15–60% of EGPA patients, a significant proportion of whom are asymptomatic and have normal electrocardiogram (ECG) and echocardiogram. Early detection and management of cardiac disease could positevely affect prognosis. Cardiovascular magnetic resonance (CMR) has emerged as the gold standard cardiac imaging technique in the evaluation of cardiomyopathies, due to its ability to reliably assess anatomy, function, and tissue characterization. Aim Purpose of this study was to assess the role of CMR in detecting cardiac disease in patients with EGPA in clinical remission. Methods A dedicated CMR protocol including functional analysis, and pre and post-contrast tissue characterization was performed in 11 patients with EGPA and the results were compared with 11 healthy subjects. Results EGPA patients had lower left ventricular ejection fraction compared to controls (56 ± 19 vs 68.7 ± 5.2, p value 0.02). Late gadolinium enhancement (LGE), representing replacement fibrosis, was positive in 9/11 (82%) patients, mainly with a non-ischemic pattern. In 3/11 (27%) patients a left ventricular thrombus was detected; in 3/11 (27%) patients myocardial edema was detected. CMR parameters of interstitial fibrosis were significantly more elevated in EGPA patients compared to controls. Conclusions Patients with EGPA in clinical remission showed a high cardiovascular burden as demonstrated by lower EF, signs of active inflammation, presence of interstitial and replacement fibrosis and intraventricular thrombosis. Further studies on wider populations are warranted to better understand how these findings could impact on prognosis and eventually guide therapy. [ABSTRACT FROM AUTHOR]

On pathological stress, Wnt signaling is reactivated and induces genes associated with cardiac remodeling and fibrosis. We have previously shown that a cell surface receptor Cdon (cell-adhesion associated, oncogene regulated) suppresses Wnt signaling to promote neuronal differentiation however its role in heart is unknown. Here, we demonstrate a critical role of Cdon in cardiac function and remodeling. Cdon is expressed and predominantly localized at intercalated disk in both mouse and human hearts. Cdon-deficient mice develop cardiac dysfunction including reduced ejection fraction and ECG abnormalities. Cdon-/- hearts exhibit increased fibrosis and up-regulation of genes associated with cardiac remodeling and fibrosis. Electrical remodeling was demonstrated by up-regulation and mislocalization of the gap junction protein, Connexin 43 (Cx43) in Cdon-/- hearts. In agreement with altered Cx43 expression, functional analysis both using Cdon-/- cardiomyocytes and shRNA-mediated knockdown in rat cardiomyocytes shows aberrant gap junction activities. Analysis of the underlying mechanism reveals that Cdon-/- hearts exhibit hyperactive Wnt signaling as evident by ß-catenin accumulation and Axin2 up-regulation. On the other hand, the treatment of rat cardiomyocytes with a Wnt activator TWS119 reduces Cdon levels and aberrant Cx43 activities, similarly to Cdon-deficient cardiomyocytes, suggesting a negative feedback between Cdon and Wnt signaling. Finally, inhibition of Wnt/ß-catenin signaling by XAV939, IWP2 or dickkopf (DKK)1 prevented Cdon depletion-induced up-regulation of collagen 1a and Cx43. Taken together, these results demonstrate that Cdon deficiency causes hyperactive Wnt signaling leading to aberrant intercellular coupling and cardiac fibrosis. Cdon exhibits great potential as a target for the treatment of cardiac fibrosis and cardiomyopathy. [ABSTRACT FROM AUTHOR]

Objectives: Acute cardiomyopathy is a health problem worldwide. Few studies have shown an association between acute cardiomyopathy and low vitamin D status. Paricalcitol, a vitamin D receptor activator, clinically benefits patients with advanced kidney disease. The effect of paricalcitol supplement on cardiac remodeling in cardiomyopathic rats is unknown. This experimental study investigated the effect of paricalcitol in rats with cardiomyopathy induced by isoproterenol.Design: Prospective, randomized, controlled experimental study.Setting: Hospital-affiliated animal research institution.Subjects: Eight-week-old male Wistar-Kyoto rats.Interventions: Male Wistar-Kyoto rats were first injected intraperitoneally with isoproterenol to create a rat model of acute cardiomyopathy. Then paricalcitol was administered intraperitoneally to isoproterenol-injected rats at a dosage of 200 ng three times a week for 3 weeks. Relevant cardiomyopathy-related variables were measured regularly in three groups of rats, controls, isoproterenol, and isoproterenol plus paricalcitol. Rat hearts were obtained for evaluation of cardiac fibrosis using Masson trichrome staining and commercially available software, and evaluation of cell transition using immunofluorescence staining analysis.Measurements and Main Results: Isoproterenol infusions generated significant cardiac fibrosis (p < 0.001). Subsequent paricalcitol treatment attenuated the isoproterenol-induced cardiac fibrosis (p = 0.006). Fluorescence showed colocalization of endothelial and fibroblast cell markers (cluster differentiation 31 and α-smooth muscle actin, respectively) in the isoproterenol-treated hearts. Paricalcitol injections attenuated the isoproterenol-induced fluorescence intensity of two cell markers (p < 0.01).Conclusions: Paricalcitol injections may ameliorate isoproterenol-induced cardiac fibrosis possibly through regulating cell transition. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis is a severe condition with limited therapeutic options and often occurs in chronic cardiovascular diseases such as hypertension and myocardial infarction. There is currently a clear need to identify novel mediators of cardiac fibrosis to facilitate the development of more effective therapeutic strategies targeting cardiac fibrosis. Integrin subunit β-like 1 (ITGBL1), an extracellular matrix protein, has previously been implicated in various fibrotic diseases. However, the precise role of ITGBL1 in regulating myocardial fibrosis remains unknown. The present study was designed to investigate whether ITGBL1 regulates angiotensin II (Ang II)-induced myocardial fibrosis in vitro and in vivo and the possible mechanism of action. It was found that the protein expressions of ITGBL1, Forkhead box Q1 (FOXQ1), and Snail were all increased significantly in fibrotic heart tissues from Ang II-infused mice and Ang II-stimulated cardiac fibroblasts, all of which were inhibited by the Ang II type I (AT1) receptor antagonist losartan. Silencing the ITGBL1/FOXQ1/Snail axis with specific siRNAs reversed Ang II-induced fibrotic effects and upregulation of FOXQ1 and Snail expressions in cardiac fibroblasts. FOXQ1 siRNA inhibited Snail expression in Ang II-induced cardiac fibroblasts. Furthermore, ITGBL1/FOXQ1 interacted with the TGF-β1 signaling to form a positive feedback loop. Our findings suggest that the extracellular matrix protein ITGBL1 mediates Ang II-induced cardiac fibrosis via the FOXQ1/Snail axis, which identifies ITGBL1 as a novel mediator of cardiac fibrosis and represents a potential therapeutic target for cardiac fibrosis. [Display omitted] • Extracellular matrix protein ITGBL1 mediates Ang II-induced cardiac fibrosis. • ITGBL1 regulates the FOXQ1/Snail axis to mediate cardiac fibrosis. • Inhibition of the FOXQ1/Snail axis prevents Ang II-induced fibrotic response. [ABSTRACT FROM AUTHOR]

Myocardial fibrosis (MF) in the remote myocardium is a feature at the micoscopic level of pathological remodeling after myocardial infarction (MI). Although pirfenidone (PFD), an antifibrotic agent, is commonly used to inhibit fibrosis in multiple organs, its clinical use is limited because of the high doses required for favorable therapeutic outcomes and various side effects. Nanodrug technology has allowed for delayed quantitative drug release and reduced the amount of medication required, improving the treatment strategy for MF. In this study, we investigated the possible therapeutic effect of peritoneal matrix-loaded pirfenidone nanodroplets (NDs) on MI fibrosis. The results showed that the Perfluoropentane-Pirfenidone@Nanodroplets-Polyethylene glycol 2000 (PFP-PFD@NDs-PEG) described in this study was successfully synthesized and demonstrated a high potential for the targeted treatment of MI. The total duration of pirfenidone release from PFP-PFD@NDs-PEG was increased by loading it into an acellular peritoneal matrix (APM). Additionally, pirfenidone inhibited the transformation of cardiac fibroblasts into cardiac myofibroblasts in vitro and reduced the synthesis and secretion of collagen I and collagen III by cardiac myofibroblasts. The combination of the APM with pirfenidone nanodroplets achieved a slow drug release and showed excellent therapeutic effects on fibrosis in MI rats. Our study confirmed the feasibility and synergistic effectiveness of the APM combined with pirfenidone nanodroplets in the treatment of fibrosis in MI rats. Moreover, our technique offers a great potential for applying nanomedicine in other biomedical fields. [ABSTRACT FROM AUTHOR]

Fibrosis is one of the crucial reasons for cardiac dysfunction after myocardial infarction (MI). Understanding the underlying molecular mechanism that causes fibrosis is crucial to developing effective therapy. Recently, OUT domain-containing 7B (OTUD7B), also called Cezanne, a multifunctional deubiquitylate, has been found to play various roles in cancer and vascular diseases and control many important signaling pathways, including inflammation, proliferation, and so on. However, whether OTUD7B plays a role in fibrosis caused by MI remains unclear. Our study aimed to explore the function of OTUD7B in cardiac fibrosis and investigate the underlying mechanism. We found that the expression of OTUD7B was downregulated in the MI rat model and cultured cardiac fibroblasts (CFs) in hypoxic conditions and after TGF-β1 treatment. In vitro, silencing OTUD7B using small interfering RNA (siRNA) increased α-SMA (smooth muscle actin α) and collagen Ⅰ levels in CFs, whereas the overexpression of OTUD7B using adenovirus decreased their expression. Mechanistically, OTUD7B could regulate the phosphorylation of focal adhesion kinase (FAK), a non-receptor tyrosine kinase that has been proved to act as a potential mediator of fibrosis, and ERK/P38 MAPK was involved in this regulation process. In vitro, overexpression of OTUD7B downregulated the phosphorylation level of FAK and then inhibited ERK/P38 phosphorylation, thus leading to decreased α-SMA and collagen Ⅰ expressions, while OTUD7B knockdown showed an opposite result. These findings suggest that OTUD7B could become a potentially effective therapeutic strategy against fibrosis after MI. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis is a pathogenic factor of many cardiovascular diseases (CVD), which seriously affects people's life and health, causing huge economic losses.Therefore, it is very significant to find an effective treatment for myocardial fibrosis. Adipokines are mainly derived from adipose tissue and have an prominent regulatory effect on glucose and lipid metabolism, inflammation, immune response and cardiovascular function. Adipose tissue is composed of a variety of cell types, including adipocytes, endothelial cells, macrophages and smooth muscle cells. Adipokines mainly include adiponectin, leptin, resistin, visfatin and omentin, which are synthesized and secreted by adipocytes. More and more evidence shows that adipokines can regulate the progress of cardiac fibrosis. This scientific review provides new ideas for targeting adipokines in the treatment of myocardial fibrosis and provides strategies for the development of new, safe, and effective pharmacological antagonists against myocardial fibrosis based on adipokines activity. [Display omitted] [ABSTRACT FROM AUTHOR]

Platelet activation is important in hypertension-induced cardiac inflammation and fibrosis. P-selectin expression significantly (P<0.05) increases when platelets are activated during hypertension. Although P-selectin recruits leukocytes to sites of inflammation, the role of P-selectin in cardiac inflammation and fibrosis remains to be elucidated. The present study aimed to investigate whether platelet-derived P-selectin promotes hypertensive cardiac inflammation and fibrosis. P-selectin knockout (P-sel KO) mice and wild-type (WT) C57BL/6 littermates were infused with angiotensin II (Ang II) at 1,500 ng/kg/min for 7 days and then cross-transplanted with platelets originating from either WT or P-sel KO mice. P-selectin expression was increased in the myocardium and plasma of hypertensive mice, and the P-sel KO mice exhibited significantly (P<0.05) reduced cardiac fibrosis. The fibrotic areas were markedly smaller in the hearts of P-sel KO mice compared with WT mice, as assessed by Masson's trichrome staining. In addition, α-smooth muscle actin and transforming growth factor β1 (TGF-β1) expression levels were decreased in the P-sel KO mice, as assessed by immunohistochemistry. Following platelet transplantation into P-sel KO mice, the number of Mac-2 (galectin-3)- and TGF-β1-positive cells was increased in mice that received WT platelets compared with those that received P-sel KO platelets, and the mRNA expression levels of collagen I and TGF-β1 were also increased. The results from the present study suggest that activated platelets secrete P-selectin to promote cardiac inflammation and fibrosis in Ang II-induced hypertension. [ABSTRACT FROM AUTHOR]