Pubblicazioni recenti - cardiac fibroblast

• Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination.
  Nat Commun

  2020 Aug;11(1):3953. doi: 10.1038/s41467-020-17740-1.
  
  Muhl Lars, Genové Guillem, Leptidis Stefanos, Liu Jianping, He Liqun, Mocci Giuseppe, Sun Ying, Gustafsson Sonja, Buyandelger Byambajav, Chivukula Indira V, Segerstolpe Åsa, Raschperger Elisabeth, Hansson Emil M, Björkegren Johan L M, Peng Xiao-Rong, Vanlandewijck Michael, Lendahl Urban, Betsholtz Christer,
  
  Abstract
  
  Many important cell types in adult vertebrates have a mesenchymal origin, including fibroblasts and vascular mural cells. Although their biological importance is undisputed, the level of mesenchymal cell heterogeneity within and between organs, while appreciated, has not been analyzed in detail. Here, we compare single-cell transcriptional profiles of fibroblasts and vascular mural cells across four murine muscular organs: heart, skeletal muscle, intestine and bladder. We reveal gene expression signatures that demarcate fibroblasts from mural cells and provide molecular signatures for cell subtype identification. We observe striking inter- and intra-organ heterogeneity amongst the fibroblasts, primarily reflecting differences in the expression of extracellular matrix components. Fibroblast subtypes localize to discrete anatomical positions offering novel predictions about physiological function(s) and regulatory signaling circuits. Our data shed new light on the diversity of poorly defined classes of cells and provide a foundation for improved understanding of their roles in physiological and pathological processes.
  
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• MicroRNA-144 regulates angiotensin II-induced cardiac fibroblast activation by targeting CREB.
  Exp Ther Med

  2020 Sep;20(3):2113-2121. doi: 10.3892/etm.2020.8901.
  
  Liu Zhi-Yong, Lu Mingjun, Liu Jing, Wang Zhao-Ning, Wang Wei-Wei, Li Yong, Song Zhi-Jing, Xu Lingling, Liu Qian, Li Feng-Hua,
  
  Abstract
  
  Cardiac fibrosis is involved in adverse cardiac remodeling and heart failure, which is the leading cause of deteriorated cardiac function. Accumulative evidence has elucidated that microRNAs (miRNAs) play important roles in the pathogenesis of cardiac fibrosis. However, the exact molecular mechanism underlying miR-144 in cardiac fibrosis remains unknown. In the present study, a transverse aortic constriction (TAC) mouse model and angiotensin II (Ang II)-induced cardiac fibroblasts (CFs) were constructed in order to investigate the expression levels of miR-144. It was demonstrated that miR-144 was significantly downregulated following pathological stimuli. CFs infected with miR-144 mimics were then used to test the effect of miR-144 on CF activation . The results revealed that overexpression of miR-144 led to a dramatically decreased proliferation and migration ability in CFs, as well as the transformation from fibroblasts to myofibroblasts, which was characterized by the decreased expression of collagen-I, collagen-III, CTGF, fibronectin and ?-SMA. By contrast, such effects could be reversed by miR-144 knockdown. Mechanistically, the bioinformatics analysis and luciferase reporter assay in the present study demonstrated that cAMP response element-binding protein (CREB) was a direct target of miR-144, and the expression of CREB was attenuated by miR-144. The results of the present study demonstrated that miR-144 played a key role in CF activation, partially by targeting CREB, which further suggested that the overexpression of miR-144 may be a promising strategy for the treatment of cardiac fibrosis.
  
  Copyright: © Liu et al.
  
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• Characterization of vortex flow in a mouse model of ventricular dyssynchrony by plane-wave ultrasound using hexplex processing.
  IEEE Trans Ultrason Ferroelectr Freq Control

  2020 Aug;PP():. doi: 10.1109/TUFFC.2020.3014844.
  
  Shekhar Akshay, Aristizabal Orlando, Fishman Glenn I, Phoon Colin K L, Ketterling Jeffrey A,
  
  Abstract
  
  The rodent heart is frequently used to study human cardiovascular disease (CVD). Although advanced cardiovascular ultrasound imaging methods are available for human clinical practice, application of these techniques to small animals remains limited due to the temporal and spatial-resolution demands. Here, an ultrasound vector-flow workflow is demonstrated that enables visualization and quantification of the complex hemodynamics within the mouse heart. Wild type (WT) and fibroblast growth factor homologous factor 2 (FHF2)-deficient mice (Fhf2KO/Y), which present with hyperthermia-induced ECG abnormalities highly reminiscent of Brugada syndrome, were used as a mouse model of human CVD. An 18-MHz linear array was used to acquire high-speed (30 kHz), plane-wave data of the left ventricle (LV) while increasing core body temperature up to 41.5°C. Hexplex (i.e., six output) processing of the raw data sets produced the output of vector-flow estimates (magnitude and phase); B-mode and color-Doppler images; Doppler spectrograms; and local time histories of vorticity and pericardium motion. Fhf2WT/Y mice had repeatable beat-to-beat cardiac function, including vortex formation during diastole, at all temperatures. In contrast, Fhf2KO/Y mice displayed dyssynchronous contractile motion that disrupted normal inflow vortex formation and impaired LV filling as temperature rose. The hexplex processing approach demonstrates the ability to visualize and quantify the interplay between hemodynamic and mechanical function in a mouse model of human CVD.
  
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• The Role of Angiogenic Inducing microRNAs in Vascular Tissue Engineering.
  Tissue Eng Part A

  2020 Aug;():. doi: 10.1089/ten.TEA.2020.0170.
  
  Ding May-Hui, Lozoya Eloy G, Rico Rene, Chew Sue Anne,
  
  Abstract
  
  Angiogenesis is an important process in tissue repair and regeneration as blood vessels are integral to supply nutrients to a functioning tissue. In this review, the application of microRNAs (miRNAs) or anti-microRNAs (anti-miRNAs) that can induce angiogenesis to aid in blood vessel formation for vascular tissue engineering in ischemic diseases such as peripheral arterial disease (PAD) and stroke, cardiac diseases and skin and bone tissue engineering are discussed. Endothelial cells form the endothelium of the blood vessel and are recognized as the primary cell type that drives angiogenesis and studied in the applications that were reviewed. Besides endothelial cells, mesenchymal stem cells (MSCs) can also play a pivotal role in these applications, specifically, by secreting growth factors or cytokines for paracrine signaling and/or as constituent cells in the new blood vessel formed. In addition to delivering miRNAs or cells transfected/transduced with miRNAs for angiogenesis and vascular tissue engineering, the utilization of extracellular vesicles (EVs), such as exosomes, microvesicles and EVs collectively, have been more recently explored. Pro-angiogenic miRNAs and anti-miRNAs contribute to angiogenesis by targeting the 3'-UTR of targets to upregulate pro-angiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and hypoxia-inducible factor-1 (HIF-1), increase the transduction of VEGF signaling through the PI3K/AKT and Ras/Raf/MEK/ERK signaling pathways such as phosphatase and tensin homolog (PTEN) or regulating the signaling of other pathways important for angiogenesis such as the Notch signaling pathway and the pathway to produce nitric oxide. In conclusion, angiogenic-inducing miRNAs and anti-miRNAs are promising tools for vascular tissue engineering for several applications; however, future work should emphasize optimizing the delivery and usage of these therapies as miRNAs can also be associated with the negative implications of cancer.
  
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• Inhibition of Aurora Kinase B attenuates fibroblast activation and pulmonary fibrosis.
  EMBO Mol Med

  2020 Aug;():e12131. doi: 10.15252/emmm.202012131.
  
  Kasam Rajesh K, Ghandikota Sudhir, Soundararajan Divyalakshmi, Reddy Geereddy B, Huang Steven K, Jegga Anil G, Madala Satish K,
  
  Abstract
  
  Fibroblast activation including proliferation, survival, and ECM production is central to initiation and maintenance of fibrotic lesions in idiopathic pulmonary fibrosis (IPF). However, druggable molecules that target fibroblast activation remain limited. In this study, we show that multiple pro-fibrotic growth factors, including TGF?, CTGF, and IGF1, increase aurora kinase B (AURKB) expression and activity in fibroblasts. Mechanistically, we demonstrate that Wilms tumor 1 (WT1) is a key transcription factor that mediates TGF?-driven AURKB upregulation in fibroblasts. Importantly, we found that inhibition of AURKB expression or activity is sufficient to attenuate fibroblast activation. We show that fibrosis induced by TGF? is highly dependent on AURKB expression and treating TGF? mice with barasertib, an AURKB inhibitor, reverses fibroblast activation, and pulmonary fibrosis. Barasertib similarly attenuated fibrosis in the bleomycin model of pulmonary fibrosis. Together, our preclinical studies provide important proof-of-concept that demonstrate barasertib as a possible intervention therapy for IPF.
  
  © 2020 The Authors. Published under the terms of the CC BY 4.0 license.
  
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• The Roles of Noncardiomyocytes in Cardiac Remodeling.
  Int J Biol Sci

  2020 ;16(13):2414-2429. doi: 10.7150/ijbs.47180.
  
  Yang Dan, Liu Han-Qing, Liu Fang-Yuan, Tang Nan, Guo Zhen, Ma Shu-Qing, An Peng, Wang Ming-Yu, Wu Hai-Ming, Yang Zheng, Fan Di, Tang Qi-Zhu,
  
  Abstract
  
  Cardiac remodeling is a common characteristic of almost all forms of heart disease, including cardiac infarction, valvular diseases, hypertension, arrhythmia, dilated cardiomyopathy and other conditions. It is not merely a simple outcome induced by an increase in the workload of cardiomyocytes (CMs). The remodeling process is accompanied by abnormalities of cardiac structure as well as disturbance of cardiac function, and emerging evidence suggests that a wide range of cells in the heart participate in the initiation and development of cardiac remodeling. Other than CMs, there are numerous noncardiomyocytes (non-CMs) that regulate the process of cardiac remodeling, such as cardiac fibroblasts and immune cells (including macrophages, lymphocytes, neutrophils, and mast cells). In this review, we summarize recent knowledge regarding the definition and significant effects of various non-CMs in the pathogenesis of cardiac remodeling, with a particular emphasis on the involved signaling mechanisms. In addition, we discuss the properties of non-CMs, which serve as targets of many cardiovascular drugs that reduce adverse cardiac remodeling.
  
  © The author(s).
  
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• Immunohistochemical analysis of periostin in the hearts of Lewis rats with experimental autoimmune myocarditis.
  J Vet Med Sci

  2020 Aug;():. doi: 10.1292/jvms.20-0225.
  
  Choi Yuna, Oh Hanseul, Ahn Meejung, Kang Taeyoung, Chun Jiyoon, Shin Taekyun, Kim Jeongtae,
  
  Abstract
  
  Periostin plays a critical role in tissue regeneration and homeostasis. The aim of this study was to evaluate the changes in periostin levels in the hearts of rats with experimental autoimmune myocarditis (EAM). Western blot analysis revealed that the expression levels of periostin and alpha-smooth muscle actin were significantly increased at day 14 post-immunization. Immunohistochemical analysis indicated that periostin was expressed in macrophages and fibroblasts in the hearts of EAM-induced rats. In conclusion, these results suggest that increased periostin expression in macrophages and fibroblasts promotes cardiac fibrosis in EAM-induced rats, potentially by enhancing immune cell infiltration. Therefore, periostin should be further investigated as a candidate therapeutic target for myocarditis.
  
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• mPGES-1 deletion attenuates isoproterenol-induced myocardial fibrosis in mice.
  J Pharmacol Exp Ther

  2020 Aug;():. doi: JPET-AR-2020-000023.
  
  Ji Shuang, Guo Rui, Wang Jing, Qian Lei, Liu Min, Xu Hu, Zhang Jiayang, Guan Youfei, Yang Guangrui, Chen Lihong,
  
  Abstract
  
  Deletion of microsomal PGE2 synthase-1 (mPGES-1) inhibits inflammation and protects against atherosclerotic vascular diseases, but displayed variable influence on pathological cardiac remodeling. Overactivation of ?-adrenergic receptors (?-ARs) causes heart dysfunction and cardiac remodeling, while the role of mPGES-1 in ?-ARs induced cardiac remodeling is unknown. Here we addressed this question using mPGES-1 knockout mice, and subjecting them to isoproterenol, a synthetic nonselective agonist for ?-ARs, at 5mg/kg/day or 15mg/kg/day to induce different degrees of cardiac remodeling in vivo. Cardiac structure and function were assessed by echocardiography 24 hours after the last of seven consecutive daily injections of isoproterenol, and cardiac fibrosis was examined by Masson trichrome stain in morphology and by real-time PCR for the expression of fibrosis related genes. The results showed that deletion of mPGES-1 had no significant effect on isoproterenol-induced cardiac dysfunction or hypertrophy. However, the cardiac fibrosis was dramatically attenuated in the mPGES-1 knockout mice after either low dose or high dose isoproterenol exposure. Furthermore, in vitro study revealed that overexpression of mPGES-1 in cultured cardiac fibroblasts increased isoproterenol induced fibrosis, while knocking-down mPGES-1 in cardiac myocytes decreased the fibrogenesis of fibroblasts. In conclusion, mPGES-1 deletion protects against isoproterenol-induced cardiac fibrosis in mice, and targeting mPGES-1 may represent a novel strategy to attenuate pathological cardiac fibrosis, induced by ?-ARs agonists. Inhibitors of mPGES-1 are being developed as alternative analgesics which are less likely to elicit cardiovascular hazards than COX-2 selective NSAIDs. We have demonstrated that deletion of mPGES-1 protects inflammatory vascular diseases and promotes post-MI survival. The role of mPGES-1 in ?-adrenergic receptors induced cardiomyopathy is unknown. Here we illustrated that deletion of mPGES-1 alleviated isoproterenol-induced cardiac fibrosis without deteriorating cardiac dysfunction. These results illustrated that targeting mPGES-1 may represent an efficacious approach to the treatment of inflammatory cardiovascular diseases.
  
  © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.
  
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• Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes.
  J Clin Med

  2020 Jul;9(8):. doi: E2457.
  
  Del Favero Giorgia, Bonifacio Alois, Rowland Teisha J, Gao Shanshan, Song Kunhua, Sergo Valter, Adler Eric D, Mestroni Luisa, Sbaizero Orfeo, Taylor Matthew R G,
  
  Abstract
  
  Danon disease is a severe X-linked disorder caused by deficiency of the lysosome-associated membrane protein-2 (LAMP-2). Clinical manifestations are phenotypically diverse and consist of hypertrophic and dilated cardiomyopathies, skeletal myopathy, retinopathy, and intellectual dysfunction. Here, we investigated the metabolic landscape of Danon disease by applying a multi-omics approach and combined structural and functional readouts provided by Raman and atomic force microscopy. Using these tools, Danon patient-derived cardiac tissue, primary fibroblasts, and human induced pluripotent stem cells differentiated into cardiomyocytes (hiPSC-CMs) were analyzed. Metabolic profiling indicated LAMP-2 deficiency promoted a switch toward glycolysis accompanied by rerouting of tryptophan metabolism. Cardiomyocytes' energetic balance and NAD+/NADH ratio appeared to be maintained despite mitochondrial aging. In turn, metabolic adaption was accompanied by a senescence-associated signature. Similarly, Danon fibroblasts appeared more stress prone and less biomechanically compliant. Overall, shaping of both morphology and metabolism contributed to the loss of cardiac biomechanical competence that characterizes the clinical progression of Danon disease.
  
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• Sigma-1 receptor ablation impedes adipocyte-like differentiation of mouse embryonic fibroblasts.
  Cell Signal

  2020 Aug;75():109732. doi: S0898-6568(20)30209-6.
  
  Yang Huan, Shen Hongtao, Li Jing, Stanford Kristin I, Guo Lian-Wang,
  
  Abstract
  
  The sigma-1 receptor (Sig1R) is a unique ligand-operated endoplasmic reticulum (ER) protein without any mammalian homolog. It has long been a pharmacological target for intervention of psychiatric disorders, and recently garnered refreshed interest for its neuroprotective potential. Though reported to modulate various intracellular events, its influence on cell identity is little known. We explored a role for Sig1R in adipocyte differentiation. We induced adipogenic differentiation of mouse embryonic fibroblasts (MEFs) with a differentiation medium. MEFs were isolated from Sigmar1 and Sigmar1 mice. The induced adipocyte-like phenotype was detected through Western blots of master transcription factors (PPAR?, CEBPA, SREBP1, SREBP2), lipogenic proteins (FABP4, ACC1, ACAT2), and Oil-Red-O staining of lipids. We found that the induced upregulation of these proteins and lipid accumulation were severely mitigated in Sigmar1 (vs Sigmar1) MEFs. Sig1R activation with a selective agonist (PRE084) increased Sig1R protein and further enhanced the induced adipocyte-like phenotype in Sigmar1 MEFs. We also determined mouse body weight gain induced by high-fat diet for 6 months, which was impeded in Sigmar1 (vs Sigmar1) male mice. In summary, genetic ablation of Sig1R impairs, and agonist activation of Sig1R enhances adipocyte-like phenotype of induced MEFs. In vivo, Sig1R ablation impedes the body weight gain of male mice on high-fat diet. This study warrants further investigation of a previously unrecognized role for Sig1R in adipocyte differentiation.
  
  Copyright © 2020 Elsevier Inc. All rights reserved.
  
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• Human pluripotent stem cell-derived cardiomyocytes as a target platform for paracrine protection by cardiac mesenchymal stromal cells.
  Sci Rep

  2020 Aug;10(1):13016. doi: 10.1038/s41598-020-69495-w.
  
  Constantinou Chrystalla, Miranda Antonio M A, Chaves Patricia, Bellahcene Mohamed, Massaia Andrea, Cheng Kevin, Samari Sara, Rothery Stephen M, Chandler Anita M, Schwarz Richard P, Harding Sian E, Punjabi Prakash, Schneider Michael D, Noseda Michela,
  
  Abstract
  
  Ischemic heart disease remains the foremost cause of death globally, with survivors at risk for subsequent heart failure. Paradoxically, cell therapies to offset cardiomyocyte loss after ischemic injury improve long-term cardiac function despite a lack of durable engraftment. An evolving consensus, inferred preponderantly from non-human models, is that transplanted cells benefit the heart via early paracrine signals. Here, we tested the impact of paracrine signals on human cardiomyocytes, using human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) as the target of mouse and human cardiac mesenchymal stromal cells (cMSC) with progenitor-like features. In co-culture and conditioned medium studies, cMSCs markedly inhibited human cardiomyocyte death. Little or no protection was conferred by mouse tail tip or human skin fibroblasts. Consistent with the results of transcriptomic profiling, functional analyses showed that the cMSC secretome suppressed apoptosis and preserved cardiac mitochondrial transmembrane potential. Protection was independent of exosomes under the conditions tested. In mice, injecting cMSC-conditioned media into the infarct border zone reduced apoptotic cardiomyocytes?>?70% locally. Thus, hPSC-CMs provide an auspicious, relevant human platform to investigate extracellular signals for cardiac muscle survival, substantiating human cardioprotection by cMSCs, and suggesting the cMSC secretome or its components as potential cell-free therapeutic products.
  
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• Commercially available transfection reagents and negative control siRNA are not inert.
  Anal Biochem

  2020 Aug;606():113828. doi: S0003-2697(20)30360-2.
  
  Kleefeldt Jan M, Pozarska Agnieszka, Nardiello Claudio, Pfeffer Tilman, Vadász István, Herold Susanne, Seeger Werner, Morty Rory E,
  
  Abstract
  
  The transfection of synthetic small interfering (si)RNA into cultured cells forms the basis of studies that use RNA interference (commonly referred to as "gene knockdown") to study the impact of loss of gene or protein expression on a biological pathway or process. In these studies, mock transfections (with transfection reagents alone), and the use of synthetic negative control (apparently inert) siRNA are both essential negative controls. This report reveals that three widely-used transfection reagents (X-tremeGENE?, HiPerFect, and Lipofectamine® 2000) and five commercially-available control siRNA (from Ambion, Sigma, Santa Cruz, Cell Signaling Technology, and Qiagen) are not inert in cell-culture studies. Both transfection reagents and control siRNA perturbed steady-state mRNA and protein levels in primary mouse lung fibroblasts and in NIH/3T3 cells (a widely-used mouse embryonic fibroblast cell-line), using components of the canonical transforming growth factor-? signaling machinery as a model system. Furthermore, transfection reagents and control siRNA reduced the viability and proliferation of both lung fibroblasts and NIH/3T3 cells. These data collectively provide a cautionary note to investigators to carefully consider the impact of control interventions, such as mock transfections and control siRNA, in RNA interference studies with synthetic siRNA.
  
  Copyright © 2020 Elsevier Inc. All rights reserved.
  
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• Interleukin-22 is elevated in the atrium and plasma of patients with atrial fibrillation and increases collagen synthesis in transforming growth factor-?1-treated cardiac fibroblasts via the JNK pathway.
  Exp Ther Med

  2020 Aug;20(2):1012-1020. doi: 10.3892/etm.2020.8778.
  
  Wu Yongxin, Tan Lihua, Shi Lei, Yang Zicong, Xue Yan, Zeng Tao, Shi Ying, Lin Yingzhong, Liu Ling,
  
  Abstract
  
  Our previous studies demonstrated that interleukin (IL)-22 is involved in cardiovascular diseases such as hypertension, cardiac fibrosis and aortic dissection. The purpose of the present study was to detect IL-22 expression in patients with atrial fibrillation (AF). Atrial tissue was collected from donors with sinus rhythm and patients with permanent AF, and the expression level of IL-22 and its receptors (IL-22R1 and IL-10R2) in both the left atrium (LA) and right atrium (RA) of each sample was detected. Blood samples were also obtained from donors with paroxysmal, persistent and permanent AF and from donors without AF history, and IL-22 levels were measured. In addition, the effects of IL-22 on collagen synthesis in TGF-?1-treated cardiac fibroblasts were investigated. IL-22R1, IL-10R2 and IL-22 expression was elevated in both the LA and RA in permanent AF patients. Elevated IL-22 expression positively correlated with the collagen areas and fibrosis marker levels in the atria of these patients. Plasma IL-22 levels were higher in AF patients compared with healthy donors and increased with increasing AF duration (from paroxysmal to persistent to permanent AF). A positive correlation was observed between IL-22 levels and TGF-?1 levels in AF patients. , recombinant mouse IL-22 treatment upregulated ?-SMA, collagen I and collagen III expression in TGF-?1-treated cardiac fibroblasts. These effects were reversed by SP600125, an inhibitor of the JNK pathway. To conclude, IL-22 levels are elevated in patients with AF and may exacerbate collagen synthesis in TGF-?1-induced cardiac fibroblasts. IL-22 may also influence AF by activating the JNK pathway.
  
  Copyright: © Wu et al.
  
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• The adaptor protein c-Cbl-associated protein (CAP) limits pro-inflammatory cytokine expression by inhibiting the NF-?B pathway.
  Int Immunopharmacol

  2020 Jul;87():106822. doi: S1567-5769(20)30900-0.
  
  Vdovenko Daria, Bachmann Marta, Wijnen Winandus J, Hottiger Michael O, Eriksson Urs, Valaperti Alan,
  
  Abstract
  
  C-Cbl-associated protein (CAP), also known as Sorbin and SH3 domain-containing protein 1 (Sorbs1) or ponsin, an adaptor protein of the insulin-signalling pathway, mediates anti-viral and anti-cytotoxic protection in acute viral heart disease. In the present study we describe a novel protective immuno-modulatory function of CAP in inflammation. Among the three members of the Sorbs family of adapter molecules, which include CAP (Sorbs1), ArgBP2 (Sorbs2), and Vinexin (Sorbs3), CAP consistently down-regulated the expression of pro-inflammatory cytokines in mouse fibroblasts, cardiomyocytes, and myeloid-derived leukocytes, after Toll-like receptor (TLR) stimulation. Upon the same TLR stimulation, ArgBP2 partially down-regulated pro-inflammatory cytokine production in mouse fibroblasts and cardiomyocytes, while Vinexin rather promoted their production. Mechanistically, CAP limited pro-inflammatory cytokine expression by suppressing the phosphorylation of Inhibitor of kappa B (I?B) kinase (I??)-? and I??-? and their downstream NF-?B-dependent signalling pathway. Molecular affinity between CAP and I??-?/ I??-? was necessary to block the NF-?B pathway. The CAP-dependent inhibitory mechanism - in vivo exclusively IL-6 inhibition - was confirmed after collecting blood from mice with systemic inflammation induced by lipopolysaccharide (LPS) and in the heart tissue collected from mice infected with the cardiotropic Coxsackievirus B3 (CVB3). Taken together, CAP down-regulates pro-inflammatory cytokines by interfering with the normal function of the NF-?B pathway. The promotion of CAP production could support the development of new strategies aiming to limit excessive and detrimental activation of the immune system.
  
  Copyright © 2020 Elsevier B.V. All rights reserved.
  
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• Si-Miao-Yong-An Decoction attenuates isoprenaline-induced myocardial fibrosis in AMPK-driven Akt/mTOR and TGF-?/SMAD3 pathways.
  Biomed Pharmacother

  2020 Jul;130():110522. doi: S0753-3322(20)30715-0.
  
  Zhao Yuqian, Sun Dejuan, Chen Yanmei, Zhan Kaixuan, Meng Qu, Zhang Xue, Zhu Lingjuan, Yao Xinsheng,
  
  Abstract
  
  Myocardial fibrosis is well-known to be the aberrant deposition of extracellular matrix (ECM), which may cause cardiac dysfunction, morbidity, and death. Traditional Chinese medicine formula Si-Miao-Yong-An Decoction (SMYAD), which is used clinically in cardiovascular diseases has been recently reported to able to resist myocardial fibrosis. The anti-fibrosis effects of SMYAD have been evaluated; however, its intricate mechanisms remain to be clarified. Here, we found that SMYAD treatment reduced the fibrosis injury and collagen fiber deposition that could improve cardiac function in isoprenaline (ISO)-induced fibrosis rat models. Combined with our systematic RNA-seq data of SMYAD treatment, we demonstrated that the remarkable up-regulation or down-regulation of several genes were closely related to the functional enrichment of TGF-? and AMPK pathways that were involved in myocardial fibrosis. Accordingly, we further explored the molecular mechanisms of SMYAD were mainly caused by AMPK activation and thereby suppressing its downstream Akt/mTOR and TGF-?/SMAD3 pathways. Moreover, we showed that the ECM deposition and secretion process were attenuated, suggesting that the fibrosis pathological features are changed. Interestingly, we found the similar AMPK-driven pathways in NIH-3T3 mouse fibroblasts treated with ISO. Taken together, these results demonstrate that SMYAD may be a new candidate agent by regulating AMPK-driven Akt/mTOR and TGF-?/SMAD3 pathways for potential therapeutic implications of myocardial fibrosis.
  
  Copyright © 2020. Published by Elsevier Masson SAS.
  
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• Isoform-specific characterization of class I histone deacetylases and their therapeutic modulation in pulmonary hypertension.
  Sci Rep

  2020 Jul;10(1):12864. doi: 10.1038/s41598-020-69737-x.
  
  Chelladurai Prakash, Dabral Swati, Basineni Sobha Rani, Chen Chien-Nien, Schmoranzer Mario, Bender Nina, Feld Christine, Nötzold René Reiner, Dobreva Gergana, Wilhelm Jochen, Jungblut Benno, Zhao Lan, Bauer Uta-Maria, Seeger Werner, Pullamsetti Soni Savai,
  
  Abstract
  
  Pharmacological modulation of class I histone deacetylases (HDAC) has been evaluated as a therapeutic strategy for pulmonary hypertension (PH) in experimental models of PH. However, information of their expression, regulation and transcriptional targets in human PH and the therapeutic potential of isoform-selective enzyme modulation are lacking. Comprehensive analysis of expression and regulation of class I HDACs (HDAC1, HDAC2, HDAC3 and HDAC8) was performed in cardiopulmonary tissues and adventitial fibroblasts isolated from pulmonary arteries (PAAF) of idiopathic pulmonary arterial hypertension (IPAH) patients and healthy donors. Cellular functions and transcriptional targets of HDAC enzymes were investigated. Therapeutic effects of pan-HDAC (Vorinostat), class-selective (VPA) and isoform-selective (CAY10398, Romidepsin, PCI34051) HDAC inhibitors were evaluated ex vivo (IPAH-PAAF, IPAH-PASMC) and in vivo (rat chronic hypoxia-induced PH and zebrafish angiogenesis). Our screening identifies dysregulation of class I HDAC isoforms in IPAH. Particularly, HDAC1 and HDAC8 were consistently increased in IPAH-PAs and IPAH-PAAFs, whereas HDAC2 and HDAC8 showed predominant localization with ACTA2-expressing cells in extensively remodeled IPAH-PAs. Hypoxia not only significantly modulated protein levels of deacetylase (HDAC8), but also significantly caused dynamic changes in the global histone lysine acetylation levels (H3K4ac, H3K9/K14ac and H3K27ac). Importantly, isoform-specific RNA-interference revealed that HDAC isoforms regulate distinct subset of transcriptome in IPAH-PAAFs. Reduced transcript levels of KLF2 in IPAH-PAAFs was augmented by HDAC8 siRNA and HDAC inhibitors, which also attenuated IPAH-associated hyperproliferation and apoptosis-resistance ex vivo, and mitigated chronic hypoxia-induced established PH in vivo, at variable degree. Class I HDAC isoforms are significantly dysregulated in human PAH. Isoform-selective HDAC inhibition is a viable approach to circumvent off-target effects.
  
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• Long-term administration of recombinant canstatin prevents adverse cardiac remodeling after myocardial infarction.
  Sci Rep

  2020 Jul;10(1):12881. doi: 10.1038/s41598-020-69736-y.
  
  Sugiyama Akira, Ito Rumi, Okada Muneyoshi, Yamawaki Hideyuki,
  
  Abstract
  
  Myocardial infarction (MI) still remains a leading cause of mortality throughout the world. An adverse cardiac remodeling, such as hypertrophy and fibrosis, in non-infarcted area leads to uncompensated heart failure with cardiac dysfunction. We previously demonstrated that canstatin, a C-terminus fragment of type IV collagen ?2 chain, exerted anti-remodeling effect against isoproterenol-induced cardiac hypertrophy model rats. In the present study, we examined whether a long-term administration of recombinant canstatin exhibits a cardioprotective effect against the adverse cardiac remodeling in MI model rats. Left anterior descending artery of male Wistar rats was ligated and recombinant mouse canstatin (20 ?g/kg/day) was intraperitoneally injected for 28 days. Long-term administration of canstatin improved survival rate and significantly inhibited left ventricular dilatation and dysfunction after MI. Canstatin significantly inhibited scar thinning in the infarcted area and significantly suppressed cardiac hypertrophy, nuclear translocation of nuclear factor of activated T-cells, interstitial fibrosis and increase of myofibroblasts in the non-infarcted area. Canstatin significantly inhibited transforming growth factor-?1-induced differentiation of rat cardiac fibroblasts into myofibroblasts. The present study for the first time demonstrated that long-term administration of recombinant canstatin exerts cardioprotective effects against adverse cardiac remodeling in MI model rats.
  
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• Beneficial Effects of Mineralocorticoid Receptor Antagonism on Myocardial Fibrosis in an Experimental Model of the Myxomatous Degeneration of the Mitral Valve.
  Int J Mol Sci

  2020 Jul;21(15):. doi: E5372.
  
  Ibarrola Jaime, Garaikoetxea Mattie, Garcia-Peña Amaia, Matilla Lara, Jover Eva, Bonnard Benjamin, Cuesta Maria, Fernández-Celis Amaya, Jaisser Frederic, López-Andrés Natalia,
  
  Abstract
  
  Mitral valve prolapse (MVP) patients develop myocardial fibrosis that is not solely explained by volume overload, but the pathophysiology has not been defined. Mineralocorticoid receptor antagonists (MRAs) improve cardiac function by decreasing cardiac fibrosis in other heart diseases. We examined the role of MRA in myocardial fibrosis associated with myxomatous degeneration of the mitral valve. Myocardial fibrosis has been analyzed in a mouse model of mitral valve myxomatous degeneration generated by pharmacological treatment with Nordexfenfluramine (NDF) in the presence of the MRA spironolactone. In vitro, adult human cardiac fibroblasts were treated with NDF and spironolactone. In an experimental mouse, MRA treatment reduced interstitial/perivascular fibrosis and collagen type I deposition. MRA administration blunted NDF-induced cardiac expression of vimentin and the profibrotic molecules galectin-3/cardiotrophin-1. In parallel, MRA blocked the increase in cardiac non-fibrillar proteins such as fibronectin, aggrecan, decorin, lumican and syndecan-4. The following effects are blocked by MRA: in vitro, in adult human cardiac fibroblasts, NDF-treatment-induced myofibroblast activation, collagen type I and proteoglycans secretion. Our findings demonstrate, for the first time, the contribution of the mineralocorticoid receptor (MR) to the development of myocardial fibrosis associated with mitral valve myxomatous degeneration. MRA could be a therapeutic approach to reduce myocardial fibrosis associated with MVP.
  
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• Melatonin ameliorates PM -induced cardiac perivascular fibrosis through regulating mitochondrial redox homeostasis.
  J Pineal Res

  2020 Jul;():e12686. doi: 10.1111/jpi.12686.
  
  Jiang Jinjin, Liang Shuang, Zhang Jingyi, Du Zhou, Xu Qing, Duan Junchao, Sun Zhiwei,
  
  Abstract
  
  Fine particulate matter (PM ) exposure is correlated with the risk of developing cardiac fibrosis. Melatonin is a major secretory product of the pineal gland that has been reported to prevent fibrosis. However, whether melatonin affects the adverse health effects of PM exposure has not been investigated. Thus, this study was aimed to investigate the protective effect of melatonin against PM -accelerated cardiac fibrosis. The echocardiography revealed that PM had impaired both systolic and diastolic cardiac function in ApoE mice. Histopathological analysis demonstrated that PM induced cardiomyocyte hypertrophy and fibrosis, particularly perivascular fibrosis. While the melatonin administration was effective in alleviating PM -induced cardiac dysfunction and fibrosis in mice. Results of electron microscopy and confocal scanning laser microscope confirmed that melatonin had restorative effects against impaired mitochondrial ultrastructure and augmented mitochondrial ROS generation in PM -treated group. Further investigation revealed melatonin administration could significantly reverse the PM -induced phenotypic modulation of cardiac fibroblasts into myofibroblasts. For the first time, our study found that melatonin effectively alleviates PM -induced cardiac dysfunction and fibrosis via inhibiting mitochondrial oxidative injury and regulating SIRT3-mediated SOD2 deacetylation. Our findings indicate that melatonin could be a therapy medicine for prevention and treatment of air pollution associated cardiac diseases.
  
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• An Optimized Protocol for Human Direct Cardiac Reprogramming.
  STAR Protoc

  2020 Jun;1(1):. doi: 100010.
  
  Garbutt Tiffany A, Zhou Yang, Keepers Benjamin, Liu Jiandong, Qian Li,
  
  Abstract
  
  Direct cardiac reprogramming, the conversion of fibroblasts into cardiomyocyte-like cells (iCMs), is an attractive approach to heal the injured heart. Here we present a new approach to human cardiac reprogramming that utilizes a polycistronic three-factor reprogramming cocktail and one microRNA. Our protocol produces cardiac Troponin T positive human iCMs (hiCMs) at an efficiency of 40%-60%, approximately double that of previous protocols, within just 2 weeks. The resulting hiCMs display cardiomyocyte-like sarcomere structure, gene expression, and calcium oscillation. For complete details on the use and execution of this protocol, please refer to Zhou et al. (2019).
  
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