Pubblicazioni recenti - cardiac fibroblast

• A tangled tale of microRNA and cardiac fibrosis.
  Clin Sci (Lond)

  2019 Nov;133(21):2217-2220. doi: 10.1042/CS20190866.
  
  Chandy Mark,
  
  Abstract
  
  Cardiac fibrosis is important for wound healing, regeneration and producing the extracellular matrix (ECM) that provides the scaffold for cells. In pathological situations, fibroblasts are activated and remodel the ECM. In volume 133, issue 17 of Clinical Science, Yang et al. discovered that the miR-214-3p/NLRC5 axis is important for fibroblast-to-myofibroblast transition (FMT) and ECM remodelling in a pressure overload model of fibrosis [Clin. Sci. (2019) 133(17), 1845-1856]. This discovery helps to explain the complicated regulation of cardiac fibrosis. It also underscores the need for more investigation into the mechanisms of cardiac fibrosis to develop better diagnostic modalities and therapeutic options in heart failure.
  
  © 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
  
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• FGF8, FGF10 and FGF receptor 2 in foreskin of children with hypospadias: an analysis of immunohistochemical expression patterns and gene transcription.
  J Pediatr Urol

  2019 Oct;():. doi: S1477-5131(19)30320-1.
  
  Haid Bernhard, Pechriggl Elisabeth, Nägele Felix, Dudas Jozsef, Webersinke Gerald, Rammer Melanie, Fritsch Helga, Oswald Josef,
  
  Abstract
  
  INTRODUCTION:
  Fibroblast growth factors (FGFs) play a crucial role in early embryogenesis of the genital tubercle and are involved in the development of hypospadias, affecting both endo- and ectodermally derived tissues. It was hypothesized that expression of FGFs could be qualitatively or quantitatively altered in skin of children with hypospadias.
  
  OBJECTIVE:
  The objective of the study was to investigate expression patterns and transcription levels of FGF8, FGF10, and FGF Receptor 2 (FGFR2) in patients with hypospadias compared to normal controls.
  
  PATIENTS AND METHODS:
  Skin samples from the ventro-lateral aspect of the foreskin of 32 patients with hypospadias (17 distal and 15 proximal, mean age 25 months) and 10 normal foreskin samples (mean age 77 months) were analyzed by immunohistochemistry. Staining, localization, and distribution of positive cells in epidermis and dermis were categorized independently by two researchers. Complementary DNA (cDNA) samples prepared from messenger RNA (mRNA) isolates of the same samples were analyzed by quantitative polymerase chain reaction (qPCR), comparing expressions of FGF8, FGF10, and FGFR2 with loading controls.
  
  RESULTS:
  Patients with hypospadias consistently showed aberrant immunohistochemical staining patterns for FGF8/FGF10/FGFR2 in epidermis and dermis compared to patients without penile malformation (p < 0.01 for all markers). qPCR displayed no difference in expression levels on mRNA level (FGFR2 p = 0.44, FGF8 p = 0.77, and FGF10 p = 0.17) comparing normal foreskin with foreskin from patients with hypospadias. Figure.
  
  DISCUSSION:
  The results point at an impact of FGF signaling during embryological development of hypospadias on skin, as an ectodermally derived tissue. Similar to the urethral development, this might be a result of mesothelial-epithelial interactions. The differing expression patterns in immunohistochemistry are not matched by a quantitative difference in marker expression on the mRNA level, putatively caused by post-translational modifications or alterations of the downstream pathway. FGFs, particularly FGF10 and FGFR2, are critically involved in wound healing.
  
  CONCLUSIONS:
  There are significant differences in localization and distribution of FGF8, FGF10, and FGFR2 in comparisons of normal foreskin to foreskin of patients with hypospadias, whereas there is no difference in the quantitative expression of these markers on the mRNA level. This confirms the notion that penile skin is affected as well by the embryological aberrations during the embryogenesis of hypospadias.
  
  Copyright © 2019 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
  
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• Direct conversion of human fibroblasts into therapeutically active vascular wall-typical mesenchymal stem cells.
  Cell Mol Life Sci

  2019 Nov;():. doi: 10.1007/s00018-019-03358-0.
  
  Steens Jennifer, Unger Kristian, Klar Lea, Neureiter Anika, Wieber Karolin, Hess Julia, Jakob Heinz G, Klump Hannes, Klein Diana,
  
  Abstract
  
  Cell-based therapies using adult stem cells are promising options for the treatment of a number of diseases including autoimmune and cardiovascular disorders. Among these, vascular wall-derived mesenchymal stem cells (VW-MSCs) might be particularly well suited for the protection and curative treatment of vascular damage because of their tissue-specific action. Here we report a novel method for the direct conversion of human skin fibroblasts towards MSCs using a VW-MSC-specific gene code (HOXB7, HOXC6 and HOXC8) that directs cell fate conversion bypassing pluripotency. This direct programming approach using either a self-inactivating (SIN) lentiviral vector expressing the VW-MSC-specific HOX-code or a tetracycline-controlled Tet-On system for doxycycline-inducible gene expressions of HOXB7, HOXC6 and HOXC8 successfully mediated the generation of VW-typical MSCs with classical MSC characteristics in vitro and in vivo. The induced VW-MSCs (iVW-MSCs) fulfilled all criteria of MSCs as defined by the International Society for Cellular Therapy (ISCT). In terms of multipotency and clonogenicity, which are important specific properties to discriminate MSCs from fibroblasts, iVW-MSCs behaved like primary ex vivo isolated VW-MSCs and shared similar molecular and DNA methylation signatures. With respect to their therapeutic potential, these cells suppressed lymphocyte proliferation in vitro, and protected mice against vascular damage in a mouse model of radiation-induced pneumopathy in vivo, as well as ex vivo cultured human lung tissue. The feasibility to obtain patient-specific VW-MSCs from fibroblasts in large amounts by a direct conversion into induced VW-MSCs could potentially open avenues towards novel, MSC-based therapies.
  
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• The relationship of circulating fibroblast growth factor 21 levels with pericardial fat: The Multi-Ethnic Study of Atherosclerosis.
  Sci Rep

  2019 Nov;9(1):16423. doi: 10.1038/s41598-019-52933-9.
  
  Magdas Arsenios, Ding Jingzhong, McClelland Robyn L, Allison Matthew A, Barter Philip J, Rye Kerry-Anne, Ong Kwok Leung,
  
  Abstract
  
  Previous small studies have reported an association between circulating fibroblast growth factor 21 (FGF21) levels and pericardial fat volume in post-menopausal women and high cardiovascular disease (CVD) risk patients. In this study, we investigated the relationship of FGF21 levels with pericardial fat volume in participants free of clinical CVD at baseline. We analysed data from 5765 men and women from the Multi-Ethnic Study of Atherosclerosis (MESA) with both pericardial fat volume and plasma FGF21 levels measured at baseline. 4746 participants had pericardial fat volume measured in at least one follow-up exam. After adjusting for confounding factors, ln-transformed FGF21 levels were positively associated with pericardial fat volume at baseline (??=?0.055, p?
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• In peripartum cardiomyopathy Plasminogen Activator Inhibitor-1 is a potential new biomarker with controversial roles.
  Cardiovasc Res

  2019 Nov;():. doi: cvz300.
  
  Ricke-Hoch Melanie, Hoes Martijn F, Pfeffer Tobias J, Schlothauer Stella, Nonhoff Justus, Haidari Susanna, Bomer Nils, Scherr Michaela, Stapel Britta, Stelling Elisabeth, Kiyan Yulia, Falk Christine, Haghikia Arash, Binah Ofer, Arany Zolt, Thum Thomas, Bauersachs Johann, van der Meer Peter, Hilfiker-Kleiner Denise,
  
  Abstract
  
  AIMS:
  Peripartum cardiomyopathy (PPCM) is a life-threatening heart disease occurring in previously healthy women. A common pathomechanism in PPCM involves the angiostatic 16kDa-prolactin (16kDa-PRL) fragment, which via NF-?B-mediated upregulation of microRNA-(miR)-146a induces vascular damage and heart failure. We analyze whether the plasminogen-activator-inhibitor-1 (PAI-1) is involved in PPCM pathophysiology.
  
  METHODS/RESULTS:
  In healthy age-matched postpartum women (PP-Ctrl, n?=?53, left-ventricular-ejection-fraction, LVEF>55%), PAI-1 plasma levels were within the normal range (21±10?ng/ml), but significantly elevated (64±38?ng/ml, p?
  CONCLUSION:
  In PPCM patients, circulating and cardiac PAI-1 expression are upregulated. While circulating PAI-1 may add 16kDa-PRL to induce vascular impairment via the uPAR/NF-?B/miR-146a pathway, experimental data suggest that cardiac PAI-1 expression seems to protect the PPCM heart from fibrosis. Thus, measuring circulating PAI-1 and miR-146a, together with an uPAR/NF-?B-activity assay could be developed into a specific diagnostic marker assay for PPCM, but unrestricted reduction of PAI-1 for therapy may not be advised.
  
  TRANSLATIONAL PERSPECTIVE:
  
  
  Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions please email: journals.permissions@oup.com.
  
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• Inhibition of microRNA-150-5p alleviates cardiac inflammation and fibrosis via targeting Smad7 in high glucose-treated cardiac fibroblasts.
  J Cell Physiol

  2019 Nov;():. doi: 10.1002/jcp.29386.
  
  Che Hui, Wang Yueqiu, Li Yang, Lv Jie, Li Hui, Liu Yining, Dong Ruixue, Sun Yongle, Xu Xiaodan, Zhao Jie, Wang Lihong,
  
  Abstract
  
  Hyperglycemia-induced cardiac fibrosis is a prominent characteristic of diabetic cardiomyopathy. Changes in proinflammatory cytokines have been shown to lead to cardiac fibrosis in patients with diabetes mellitus. This study aimed to investigate the role of miR-150-5p in mediating cardiac inflammation and fibrosis in cardiac fibroblasts (CFs). Herein, we found that high-glucose (HG) treatment significantly induced cardiac inflammation, as manifested by increased proinflammatory cytokine production (IL-1?) and NF-?B activity in CFs. Moreover, HG markedly aggravated cardiac fibrosis and increased levels of fibrotic markers (CTGF, FN, ?-SMA) and extracellular matrix proteins (Col-I, Col-III) in CFs. At the same time, HG disturbed the TGF-?1/Smad signaling pathway, as evidenced by increases in TGF-?1 and p-Smad2/3 levels and decreases in Smad7 levels in CFs. Furthermore, we found that miR-150-5p was upregulated by HG, which negatively regulated Smad7 expression at the posttranscription level. Further study demonstrated that cardiac inflammation and fibrosis in CFs were corrected following miR-150-5p knockdown, but exacerbated by miR-150-5p overexpression. These data indicated that miR-150-5p inhibition could ameliorate NF-?B-related inflammation and TGF-?1/Smad-induced cardiac fibrosis through targeting Smad7. Thus, miR-150-5p may be a novel promising target for treating diabetic cardiomyopathy.
  
  © 2019 Wiley Periodicals, Inc.
  
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• Effect of storage conditions and activation on growth factor concentration in platelet-rich plasma.
  J Orthop Res

  2019 Nov;():. doi: 10.1002/jor.24520.
  
  Kim Joong Il, Bae Hyun Cheol, Park Hee Jung, Lee Myung Chul, Han Hyuk Soo,
  
  Abstract
  
  This study aimed to evaluate growth factor concentration in PRP (leukocyte-rich PRP) based on storage temperature, duration of storage, and method of activation. PRP samples were stored at 24? (room temperature group), 4? (refrigerator group), and -70? (deep-freezer group). In each temperature, four aliquots were prepared based on the time of analysis (immediately, 1, 3, 7 days after preparation). After storage, concentrations of platelet-derived growth factor-AA (PDGF-AA), transforming growth factor-beta (TGF- ?), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), and fibroblast growth factor-basic (FGF-B) were assessed with/without activation using Quantikine colorimetric sandwich immunoassay kits. PRP was activated with 10% Triton-X for PDGF-AA, VEGF, FGF-B, IGF-1 measurement and sonication for TGF-?1 measurement. Without activation, PDGF-AA concentration was highest on day 7 in the room temperature group. With activation, concentration of PDGF-AA was constant over the observation period at all temperatures. Without activation, TGF-?1 concentration remained negligible over the observation period at all temperatures. However, with activation, TGF-?1 gradually increased to its highest concentration on day 7 at all temperatures. Over the observation period, VEGF and IGF-1 concentrations were constant with and without activation at all temperatures. Without activation, FGF-B concentration increased, with the highest concentration observed on day 7 in the deep-freezer group. With activation, FGF-B concentration decreased after day 1 in the room temperature group. Growth factor concentration in PRP differed significantly based on storage temperature, duration of storage, and method of activation. Appropriate storage conditions and activation are important to optimize its effects for desired clinical outcomes. This article is protected by copyright. All rights reserved.
  
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• Non-genomic Effects of Estrogen on Cell Homeostasis and Remodeling With Special Focus on Cardiac Ischemia/Reperfusion Injury.
  Front Endocrinol (Lausanne)

  2019 ;10():733. doi: 10.3389/fendo.2019.00733.
  
  Puglisi Rossella, Mattia Gianfranco, Carè Alessandra, Marano Giuseppe, Malorni Walter, Matarrese Paola,
  
  Abstract
  
  This review takes into consideration the main mechanisms involved in cellular remodeling following an ischemic injury, with special focus on the possible role played by non-genomic estrogen effects. Sex differences have also been considered. In fact, cardiac ischemic events induce damage to different cellular components of the heart, such as cardiomyocytes, vascular cells, endothelial cells, and cardiac fibroblasts. The ability of the cardiovascular system to counteract an ischemic insult is orchestrated by these cell types and is carried out thanks to a number of complex molecular pathways, including genomic (slow) or non-genomic (fast) effects of estrogen. These pathways are probably responsible for differences observed between the two sexes. Literature suggests that male and female hearts, and, more in general, cardiovascular system cells, show significant differences in many parameters under both physiological and pathological conditions. In particular, many experimental studies dealing with sex differences in the cardiovascular system suggest a higher ability of females to respond to environmental insults in comparison with males. For instance, as cells from females are more effective in counteracting the ischemia/reperfusion injury if compared with males, a role for estrogen in this sex disparity has been hypothesized. However, the possible involvement of estrogen-dependent non-genomic effects on the cardiovascular system is still under debate. Further experimental studies, including sex-specific studies, are needed in order to shed further light on this matter.
  
  Copyright © 2019 Puglisi, Mattia, Carè, Marano, Malorni and Matarrese.
  
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• LncRNA FAF inhibits fibrosis induced by angiotensinogen II via the TGF?1-P-Smad2/3 signalling by targeting FGF9 in cardiac fibroblasts.
  Biochem Biophys Res Commun

  2019 Nov;():. doi: S0006-291X(19)32085-6.
  
  Sun Jiateng, Wang Zimu, Shi Haojie, Gu Lingfeng, Wang Sibo, Wang Hao, Li Yafei, Wei Tianwen, Wang Qiming, Wang Liansheng,
  
  Abstract
  
  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 ?1 (TGF?1) 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 TGF?1-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 TGF?1-P-Smad2/3 signalling by targeting FGF9 in CFs.
  
  Copyright © 2019 Elsevier Inc. All rights reserved.
  
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• MicroRNA-21 deficiency attenuated atherogenesis and decreased macrophage infiltration by targeting Dusp-8.
  Atherosclerosis

  2019 Oct;291():78-86. doi: S0021-9150(19)31520-5.
  
  Gao Lin, Zeng Huasu, Zhang Tiantian, Mao Chengyu, Wang Yue, Han Zhihua, Chen Kan, Zhang Junfeng, Fan Yuqi, Gu Jun, Wang Changqian,
  
  Abstract
  
  BACKGROUND AND AIMS:
  Atherosclerosis is a chronic inflammatory disorder mediated by macrophage activation. MicroRNA-21 (miR-21) is a key regulator in the macrophage inflammatory response. However, the functional role of miR-21 in atherogenesis is far from clear.
  
  METHODS AND RESULTS:
  Here, we report that miR-21 is significantly upregulated in mouse atherosclerotic plaques and peripheral monocytes from patients with coronary artery disease. Compared with miR-21apoE mice (apoE mice), miR-21apoE (double knockout, DKO) mice showed less atherosclerotic lesions, reduced presence of macrophages, decreased smooth muscle cells(SMC) and collagen content in the aorta. We further explored the role of miR-21 in macrophage activation in vitro. Bone marrow-derived macrophages (BMDMs) from DKO mice not only exhibit impaired function of migration induced by chemokine (C-C motif) ligand 2 (CCL2) but also a weakened macrophage-endothelium interaction activated by tumor necrosis factor-? (TNF-?). However, atherogenic inflammatory cytokine secretion was not affected by miR-21 in vitro or in vivo. Additionally, miR-21 knockdown in BMDMs directly derepressed the expression of dual specificity protein phosphatase 8 (Dusp-8), a previously validated miR-21 target in cardiac fibroblasts, which negatively regulates mitogen-activated protein kinase (MAPK) signaling, particularly the p38-and c-Jun N-terminal kinase (JNK)-related signaling pathways.
  
  CONCLUSIONS:
  These data demonstrate that inhibition of miR-21 may restrict the formation of atherosclerotic plaques partly by regulating macrophage migration and adhesion, while, reduced SMCs and collagen content in plaques may lead to a less stable phenotype with the progression of atherosclerosis. Thus, the absence of miR-21 reduces atherosclerotic lesions but may not represent all benefit in atherosclerosis development.
  
  Copyright © 2019 Elsevier B.V. All rights reserved.
  
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• YY1 mediates TGF-?1-induced EMT and pro-fibrogenesis in alveolar epithelial cells.
  Respir Res

  2019 Nov;20(1):249. doi: 10.1186/s12931-019-1223-7.
  
  Zhang Chuyi, Zhu Xiaoping, Hua Yifei, Zhao Qian, Wang Kaijing, Zhen Lixiao, Wang Guangxue, Lü Jinhui, Luo An, Cho William C, Lin Xin, Yu Zuoren,
  
  Abstract
  
  Pulmonary fibrosis is a chronic, progressive lung disease associated with lung damage and scarring. The pathological mechanism causing pulmonary fibrosis remains unknown. Emerging evidence suggests prominent roles of epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AECs) in myofibroblast formation and progressive pulmonary fibrosis. Our previous work has demonstrated the regulation of YY1 in idiopathic pulmonary fibrosis and pathogenesis of fibroid lung. However, the specific function of YY1 in AECs during the pathogenesis of pulmonary fibrosis is yet to be determined. Herein, we found the higher level of YY1 in primary fibroblasts than that in primary epithelial cells from the lung of mouse. A549 and BEAS-2B cells, serving as models for type II alveolar pulmonary epithelium in vitro, were used to determine the function of YY1 during EMT of AECs. TGF-?-induced activation of the pro-fibrotic program was applied to determine the role YY1 may play in pro-fibrogenesis of type II alveolar epithelial cells. Upregulation of YY1 was associated with EMT and pro-fibrotic phenotype induced by TGF-? treatment. Targeted knockdown of YY1 abrogated the EMT induction by TGF-? treatment. Enforced expression of YY1 can partly mimic the TGF-?-induced pro-fibrotic change in either A549 cell line or primary alveolar epithelial cells, indicating the induction of YY1 expression may mediate the TGF-?-induced EMT and pro-fibrosis. In addition, the translocation of NF-?B p65 from the cytoplasm to the nucleus was demonstrated in A549 cells after TGF-? treatment and/or YY1 overexpression, suggesting that NF-?B-YY1 signaling pathway regulates pulmonary fibrotic progression in lung epithelial cells. These findings will shed light on the better understanding of mechanisms regulating pro-fibrogenesis in AECs and pathogenesis of lung fibrosis.
  
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• Collagen receptor cross-talk determines ?-smooth muscle actin-dependent collagen gene expression in angiotensin II-stimulated cardiac fibroblasts.
  J Biol Chem

  2019 Nov;():. doi: jbc.RA119.009744.
  
  V Harikrishnan, Titus Allen Sam, Cowling Randy T, Kailasam Shivakumar,
  
  Abstract
  
  Excessive collagen deposition by myofibroblasts during adverse cardiac remodeling leads to myocardial fibrosis that can compromise cardiac function. Unraveling the mechanisms underlying collagen gene expression in cardiac myofibroblasts is therefore an important clinical goal. The collagen receptors, discoidin domain receptor 2 (DDR2), a collagen-specific receptor tyrosine kinase, and integrin-?1, are reported to mediate tissue fibrosis. Here, we probed the role of DDR2-integrin-?1 cross-talk in the regulation of collagen alpha1(I) gene expression in angiotensin II (Ang II)-stimulated cardiac fibroblasts. Results from gene silencing/overexpression approaches, electrophoretic mobility shift assays and ChIP revealed that DDR2 acts via extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (ERK1/2 MAPK)-dependent transforming growth factor-?1 (TGF-?1) signaling to activate activator protein-1 (AP-1) that in turn transcriptionally enhances the expression of collagen-binding integrin-?1 in Ang II-stimulated cardiac fibroblasts. The DDR2-integrin-?1 link was also evident in spontaneously hypertensive rats and DDR2-knockout mice. Further, DDR2 acted via integrin-?1 to regulate ?-smooth muscle actin (?-SMA) and collagen type I expression in Ang II-exposed cardiac fibroblasts. Downstream of the DDR2-integrin-?1 axis, ?-SMA was found to regulate collagen alpha1(I) gene expression via the Ca2+ channel, transient receptor potential cation channel subfamily C member 6 (TRPC6), and the profibrotic transcription factor, Yes-associated protein (YAP). This finding indicated that fibroblast-to-myofibroblast conversion is mechanistically coupled to collagen expression. The observation that collagen receptor cross-talk underlies ?-SMA-dependent collagen type I expression in cardiac fibroblasts expands our understanding of the complex mechanisms involved in collagen gene expression in the heart, and may be relevant to cardiac fibrogenesis.
  
  Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
  
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• [Effect of microRNA-133b on Myocardial Fibrosis].
  Zhongguo Yi Xue Ke Xue Yuan Xue Bao

  2019 Oct;41(5):589-594. doi: 10.3881/j.issn.1000-503X.10941.
  
  Zhang Song Lin, Fan Fen Ling, Wei Feng, Wang Jun, Zhang Yu Shun,
  
  Abstract
  
  Objective To investigate the effect of microRNA-133b(miR-133b)on cardiac fibrosis and its mechanism.Methods Human cardiac fibroblasts(CFs)were harvested.The proliferation of CFs was detected by CCK8 during the overexpression and knock-down of miR-133b.The expressions of connective tissue growth factor(CTGF),?-smooth muscle actin(?-SMA),collagen ?,and collagen ? were detected with qRT-PCR and Western blot analysis after miR-133b overexpression or downexpression.Target genes of miR-133b were predicted by bioinformatics software.Dual-luciferase activity assay were used to verify a target gene of miR-133b.Results qRT-PCR showed that the expression level of miR-133b in the miR-133b mimic group was significantly higher than that in the negative control group(=26.219,=0.000).The expression level of miR-133b in the miR-133b inhibitor group was significantly lower than that in the negative control group(=6.738,=0.003).After 21,45,69,93,and 117 hours of transfection,the proliferation ability of CFs significantly decreased in the miR-133b mimic group but significantly increased in the miR-133b group(all <0.05,compared with the negative control group).After overexpression of miR-133b,the mRNA and protein levels of CTGF(=9.213,=0.001;=8.195,=0.001),?-SMA(=6.511, =0.003;=4.434,=0.011),collagen?(=3.172,=0.034;=4.053,=0.015)and collagen ?(=6.404,=0.003;=5.319,=0.006)were significantly down-regulated.After the expression of miR-133b was knocked down,the mRNA and protein levels of CTGF(=9.439,=0.001;=14.100,=0.000),?-SMA(=4.519,=0.011;=4.377,=0.012),collagen ?(=5.966,=0.004;=5.514,=0.005)and collagen ?(=4.622,=0.010;=4.996,=0.008)were significantly increased.The relative luciferase activity of the cells co-transfected with miR-133b mimic and WT 3'UTR expression vector was significantly lower than that of the cells co-transfected with mimic control and WT 3'UTR expression vectors(=5.654,=0.005);however,there was no significant difference in relative luciferase activity between cells co-transfected with miR-133b mimic and MUT 3'UTR expression vectors and cells co-transfected with mimic control and MUT 3'UTR expression vectors(=0.380,=0.724).Conclusion miR-133b may affect the activation and proliferation of CFs by targeting CTGF and thus improve cardiac fibrosis.
  
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• Transcriptome-wide association study reveals candidate causal genes for lung cancer.
  Int J Cancer

  2019 Nov;():. doi: 10.1002/ijc.32771.
  
  Bossé Yohan, Li Zhonglin, Xia Jun, Manem Venkata, Carreras-Torres Robert, Gabriel Aurélie, Gaudreault Nathalie, Albanes Demetrius, Aldrich Melinda C, Andrew Angeline, Arnold Susanne, Bickeböller Heike, Bojesen Stig E, Brennan Paul, Brunnstrom Hans, Caporaso Neil, Chen Chu, Christiani David C, Field John K, Goodman Gary, Grankvist Kjell, Houlston Richard, Johansson Mattias, Johansson Mikael, Kiemeney Lambertus A, Lam Stephen, Landi Maria Teresa, Lazarus Philip, Le Marchand Loic, Liu Geoffrey, Melander Olle, Rennert Gadi, Risch Angela, Rosenberg Susan M, Schabath Matthew B, Shete Sanjay, Song Zhuoyi, Stevens Victoria L, Tardon Adonina, Wichmann H-Erich, Woll Penella, Zienolddiny Shan, Obeidat Ma'en, Timens Wim, Hung Rayjean J, Joubert Philippe, Amos Christopher I, McKay James D,
  
  Abstract
  
  We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of this study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n=1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma, small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (P =1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (P =3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (P =6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influence lung cancer risk. This article is protected by copyright. All rights reserved.
  
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• LncRNA- contributes to cardiac fibrosis through --HuR complex in mouse myocardial infarction.
  Theranostics

  2019 ;9(24):7282-7297. doi: 10.7150/thno.33920.
  
  Hao Kaili, Lei Wei, Wu Hongchun, Wu Jie, Yang Zhuangzhuang, Yan Shiping, Lu Xing-Ai, Li Jingjing, Xia Xue, Han Xinglong, Deng Wenbo, Zhong Guisheng, Zhao Zhen-Ao, Hu Shijun,
  
  Abstract
  
  : As a hallmark of various heart diseases, cardiac fibrosis ultimately leads to end-stage heart failure. Anti-fibrosis is a potential therapeutic strategy for heart failure. Long noncoding RNAs (lncRNAs) have emerged as critical regulators of heart diseases that promise to serve as therapeutic targets. However, few lncRNAs have been directly implicated in cardiac fibrosis. : The lncRNA expression profiles were assessed by microarray in cardiac fibrotic and remote ventricular tissues in mice with myocardial infarction. The mechanisms and functional significance of lncRNA- in cardiac fibrosis were further investigated with both and models. : We identified 389 differentially expressed lncRNAs in cardiac fibrotic and remote ventricular tissues in mice with myocardial infarction. Among them, a lncRNA () we named was enriched in the nuclei of fibroblasts, and elevated in both myocardial infarction and TGF-?-induced cardiac fibrosis. Knockdown of prevented TGF-?-induced fibroblast-myofibroblast transition, aberrant cell proliferation and secretion of extracellular matrix proteins , and mended the impaired cardiac function in mice suffering myocardial infarction. studies indicated that knockdown of significantly inhibited the expression of its neighboring gene , and vice versa. The overexpression obviously disturbed the regulatory effects of shRNAs in both the cultured cardiac fibroblasts and myocardial infarction-induced fibrosis. Dual-Luciferase assay demonstrated that and mRNA stabilized each other via their complementary binding at the 3'-end. RNA electrophoretic mobility shift assay and RNA immunoprecipitation assay indicated that RNA binding protein HuR could bind to - RNA duplex, whereas the knockdown of dramatically reduced the stabilization of and mRNAs, down-regulated their expression in cardiac fibroblasts, and thus inhibited TGF-?-induced fibrosis. The overexpression partially restrained the phenotype change of cardiac fibroblasts induced by shRNAs, but not that induced by shRNAs. : Our study identifies as a critical regulator of cardiac fibrosis, and demonstrates --HuR complex-mediated mRNA stability is the underlying mechanism of -regulated cardiac fibrosis. Fibroblast-enriched could represent a novel target for anti-fibrotic therapy in heart diseases.
  
  © The author(s).
  
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• Invited review: hypertension and atrial fibrillation: epidemiology, pathophysiology, and implications for management.
  J Hum Hypertens

  2019 Nov;():. doi: 10.1038/s41371-019-0279-7.
  
  Gumprecht Jakub, Domek Magdalena, Lip Gregory Y H, Shantsila Alena,
  
  Abstract
  
  Hypertension affects around half of the adult population worldwide, being one of the most common cardiovascular disorders. On a population basis, high blood pressure is considered to be the major independent risk factor for atrial fibrillation (AF). The incidence of both diseases has increased significantly in the recent decades and it is expected to continuously surge in the following years. Due to close relation between the both diseases and their frequent coexistence, hypertension and AF become major health priorities. The multidirectional linking between raised blood pressure and AF is based on complex associations including structural, hemodynamic, neuroendocrine, and autonomic mechanisms. Hypertension provokes excessive fibroblasts proliferation and increased collagen accumulation. It also stimulates cardiomyocytes apoptosis and inflammation, leading to diffused fibrosis and left ventricular hypertrophy development. This is mainly driven by renin-angiotensin-aldosterone system (RAAS) activation, and autonomic dysregulation. Moreover, exposure on long-term stretch due to hypertension causes arterial stiffness with subsequent systolic and diastolic function loss resulting in further heart muscle remodeling. All these pathological changes combined seem influence on myocardial electrical activity, triggering AF development. Given the prevalence and frequent lack of symptoms of both disorders, opportunistic arrhythmia screening in hypertensive patients is needed. In all individuals with established diagnosis of AF, adequate anticoagulation has to be considered for stroke prevention. Blood pressure control is also an essential component of a holistic approach to AF care.
  
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• TGF-? induces a heart failure phenotype via fibroblasts exosome signaling.
  Heliyon

  2019 Oct;5(10):e02633. doi: 10.1016/j.heliyon.2019.e02633.
  
  Basma Hesham, Johanson Adelaide N, Dhar Kajari, Anderson Daniel, Qiu Fang, Rennard Stephen, Lowes Brian D,
  
  Abstract
  
  Purpose:
  The mechanisms for persistent and progressive loss of myocardial function in advanced heart failure (HF) remain incompletely characterized. In the current study, we sought to determine the impact of TGF-? on fibroblasts transcriptional profiles and assess if exosomes from TGF-? treated fibroblasts could induce a heart failure phenotype in co-cultured cardiomyocytes.
  
  Method:
  Normal heart fibroblasts were treated with TGF-? with a final conc. of 2.5 ng/ml in serum free media. HF fibroblasts were also obtained from patients undergoing implantation of left ventricular assist devices. Exosomes were collected using three-step ultracentrifugation. Cardiomyocytes were co-cultured with exosomes from TGF-?-treated, HF and control fibroblasts. RNA was extracted from the fibroblasts, exosomes, and the cardiomyocytes for a targeted panel of genes using Ion AmpliSeq. Fibroblast function was evaluated by collagen gel contraction.
  
  Results:
  Fibroblasts treated with TGF-? differentially express 21 of the 140 genes in our targeted panel. These fibroblasts exhibit enhanced collagen gel contraction similar to HF fibroblasts. Fifty of these targeted genes were also differentially expressed in fibroblast exosomes. Pathway analysis of these transcriptional changes suggest hypertrophic signaling to cardiac muscle. Cardiomyocytes, co-cultured with exosomes from TGF- ? treated fibroblasts or heart failure patients, differentially expressed 40 genes compared to controls. Cardiomyocytes co-cultured with exosomes of TGF-? treated fibroblasts induced a molecular phenotype similar to cardiomyocytes co-cultured with exosomes from HF fibroblasts. These changes involve contractile proteins, adrenergic receptors, calcium signaling, metabolism and cell renewal.
  
  Conclusion:
  TGF-? induces broad transcriptional changes in fibroblasts as well as their exosomes. These exosomes induce a heart failure phenotype in cardiomyocytes. Exosome signaling from fibroblasts likely contributes to disease progression in heart failure.
  
  © 2019 The Authors. Published by Elsevier Ltd.
  
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• Generation of a large-scale vascular bed for the creation of three-dimensional cardiac tissue.
  Regen Ther

  2019 Dec;11():316-323. doi: 10.1016/j.reth.2019.10.001.
  
  Inui Akitoshi, Sekine Hidekazu, Sano Kazunori, Dobashi Izumi, Yoshida Azumi, Matsuura Katsuhisa, Kobayashi Eiji, Ono Minoru, Shimizu Tatsuya,
  
  Abstract
  
  Introduction:
  The definitive treatment for severe heart failure is transplantation. However, only a small number of heart transplants are performed each year due to donor shortages. Therefore, novel treatment approaches based on artificial organs or regenerative therapy are being developed as alternatives. We have developed a technology known as cell sheet-based tissue engineering that enables the fabrication of functional three-dimensional (3D) tissue. Here, we report a new technique for engineering human cardiac tissue with perfusable blood vessels. Our method involved the layering of cardiac cell sheets derived from human induced pluripotent stem cells (hiPSCs) on a vascular bed derived from porcine small intestinal tissue.
  
  Methods:
  For the vascular bed, a segment of porcine small intestine was harvested together with a branch of the superior mesenteric artery and a branch of the superior mesenteric vein. The small intestinal tissue was incised longitudinally, and the mucosa was resected. Human cardiomyocytes derived from hiPSCs were co-cultured with endothelial cells and fibroblasts on a temperature-responsive dish and harvested as a cardiac cell sheet. A triple-layer of cardiac cell sheets was placed onto the vascular bed, and the resulting construct was subjected to perfusion culture in a bioreactor system.
  
  Results:
  The cardiac tissue on the vascular bed pulsated spontaneously and synchronously after one day of perfusion culture. Electrophysiological recordings revealed regular action potentials and a beating rate of 105 ± 13/min (n = 8). Furthermore, immunostaining experiments detected partial connection of the blood vessels between the vascular bed and cardiac cell sheets.
  
  Conclusions:
  We succeeded in engineering spontaneously beating 3D cardiac tissue using human cardiac cell sheets and a vascular bed derived from porcine small intestine. Further development of this method might allow the fabrication of functional cardiac tissue that could be used in the treatment of severe heart failure.
  
  © 2019 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.
  
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• Cardiovascular autonomic reflex tests and serum FGF21 levels in overweight and normal-weight men and women.
  Arch Physiol Biochem

  2019 Nov;():1-5. doi: 10.1080/13813455.2019.1683586.
  
  Jezdimirovic Tatjana, Stajer Valdemar, OstojicV Sergej M,
  
  Abstract
  
  We evaluated cardiovascular autonomic reflexes and serum fibroblast growth factor 21 (FGF21), a surrogate marker of mitochondrial function, in a cohort of overweight and normal-weight adults (?=?42). Indices of autonomic function were monitored during supine rest, autonomic reflex tests and submaximal clinical exercise test, with heart rate variables and blood pressure measured with an automatic system. Markers of sympathetic dominance were accentuated in overweight adults, including elevated resting low-frequency to the high-frequency ratio for heart rate variability (203?±?227 96?±?42; ?=?.01), and handgrip diastolic blood pressure (36?±?15?mmHg 25?±?12?mmHg; ?=?.01). A weak non-significant trend has been found for a negative correlation between blood pressure responses to isometric handgrip test and FGF21 in the overweight group ( = -0.37; ?=?.09). Excess body weight appears to trigger sympathetic overactivity in overweight adults, yet autonomic dysregulation might not be associated with notable changes in serum FGF21.
  
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• Heart failure as interstitial cancer: emergence of a malignant fibroblast phenotype.
  Nat Rev Cardiol

  2019 Nov;():. doi: 10.1038/s41569-019-0286-y.
  
  Oatmen Kelsie E, Cull Elizabeth, Spinale Francis G,
  
  Abstract
  
  A prolonged state of left ventricular pressure overload, commonly caused by hypertension and aortic valve disease, promotes remodelling of the myocardium that can progress to heart failure with preserved ejection fraction (HFpEF). In animal models, a major factor driving progression from pressure-overload hypertrophy (POH) to HFpEF is the activation and proliferation of an abnormal fibroblast phenotype that is resistant to apoptosis, degrades normal stromal matrix and is replaced with a fibrotic matrix structure. A similar fibroblast phenotype has been identified in the stroma of solid cancers. This cancer-associated fibroblast drives tumour growth and invasion. The proliferation and expansion of these abnormal fibroblast populations in both HFpEF and cancer contribute to progression of disease. In early-phase clinical trials, chemotherapeutic agents targeting cancer-associated fibroblasts had antitumour properties. In this Perspectives article, we postulate that, because the abnormal fibroblast populations in POH and cancer have identical characteristics, chemotherapeutic agents targeting the POH-related fibroblast might attenuate the development of myocardial fibrosis, a pathophysiological hallmark of HFpEF. These agents must be designed to target the abnormal fibroblasts with high specificity because many classes of chemotherapeutic drugs can themselves cause myocardial dysfunction and heart failure.
  
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