Pubblicazioni recenti - cardiac fibroblast

• Molecular mechanisms of circular RNAs, transforming growth factor-?, and long noncoding RNAs in hepatocellular carcinoma.
  Cancer Med

  2019 Sep;():. doi: 10.1002/cam4.2553.
  
  Shang Wenkang, Adzika Gabriel Komla, Li Yujie, Huang Qike, Ding Ningding, Chinembiri Bianca, Rashid Mohammad Sajjad Ibn, Machuki Jeremiah Ong'achwa,
  
  Abstract
  
  At the heart of hepatocellular carcinoma (HCC) lies disruption of signaling pathways at the level of molecules, genes, and cells. Non-coding RNAs (ncRNAs) have been implicated in the disease progression of HCC. For instance, dysregulated expression of circular RNAs (circRNAs) has been observed in patients with HCC. As such, these RNAs are potential therapeutic targets and diagnostic markers for HCC. Long non-coding RNAs (lncRNAs), a type of ncRNA, have also been recognized to participate in the initiation and progression of HCC. Transforming growth factor-beta (TGF-?) is another element which is now recognized to play crucial roles in HCC. It has been implicated in many biological processes such as survival, immune surveillance, and cell proliferation. In HCC, TGF-? promotes disease progression by two mechanisms: an intrinsic signaling pathway and the extrinsic pathway. Through these pathways, it modulates various microenvironment factors such as inflammatory mediators and fibroblasts. An interesting yet-to-be resolved concept is whether the HCC-promoting role of TGF-? pathways is limited to a subset of HCC patients or it is involved in the whole process of HCC development. This review summarizes recent advancements to highlight the roles of circRNAs, lncRNAs, and TGF-? in HCC.
  
  © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
  
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• Spatiotemporal delivery of basic fibroblast growth factor to directly and simultaneously attenuate cardiac fibrosis and promote cardiac tissue vascularization following myocardial infarction.
  J Control Release

  2019 Sep;():. doi: S0168-3659(19)30538-3.
  
  Fan Zhaobo, Xu Zhaobin, Niu Hong, Sui Yang, Li Haichang, Ma Jianjie, Guan Jianjun,
  
  Abstract
  
  Following myocardial infarction (MI), the destruction of vasculature in the infarcted heart muscle and progression of cardiac fibrosis lead to cardiac function deterioration. Vascularization of the damaged tissue and prevention of cardiac fibrosis represent promising strategies to improve cardiac function. Herein we have developed a bFGF release system with suitable release kinetics to simultaneously achieve the two goals. The release system was based on an injectable, thermosensitive, and fast gelation hydrogel and bFGF. The hydrogel had gelation time <7?s. It can quickly solidify upon injection into tissue so as to increase drug retention in the tissue. Hydrogel complex modulus can be tuned by hydrogel solution concentration. The complex modulus of 176.6?Pa and lower allowed cardiac fibroblast to maintain its phenotype. Bioactive bFGF was able to gradually release from the hydrogel for 4?weeks. The released bFGF promoted cardiac fibroblast survival under ischemic conditions mimicking those of the infarcted hearts. It also attenuated cardiac fibroblasts from differentiating into myofibroblasts in the presence of TGF? when tested in 3D collagen model mimicking the scenario when the bFGF release system was injected into hearts. Furthermore, the released bFGF stimulated human umbilical endothelial cells to form endothelial lumen. After 4?weeks of implantation into infarcted hearts, the bFGF release system significantly increased blood vessel density, decreased myofibroblast density and collagen content, augmented cardiac cell survival/proliferation, and reduced macrophage density. In addition, the bFGF release system significantly increased cardiac function. These results demonstrate that delivery of bFGF with appropriate release kinetics alone may represent an efficient approach to control cardiac remodeling after MI.
  
  Copyright © 2018. Published by Elsevier B.V.
  
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• The axis of local cardiac endogenous Klotho-TGF-?1-Wnt signaling mediates cardiac fibrosis in human.
  J Mol Cell Cardiol

  2019 Sep;():. doi: S0022-2828(19)30187-7.
  
  Liu Qinghua, Zhu Lang-Jing, Waaga-Gasser Ana Maria, Ding Yan, Cao Minghua, Jadhav Shreyas J, Kirollos Sandra, Shekar Prem S, Padera Robert F, Chang Yu-Chun, Xu Xingbo, Zeisberg Elisabeth M, Charytan David M, Hsiao Li-Li,
  
  Abstract
  
  BACKGROUND:
  Cardiovascular fibrosis is a major contributor to cardiovascular disease, the primary cause of death in patients with chronic kidney disease (CKD). We previously reported expression of endogenous Klotho in human arteries, and that CKD is a state of Klotho deficiency, resulting in vascular calcification, but myocardial expression of Klotho is poorly understood. This study aimed to further clarify endogenous Klotho's functional roles in cardiac fibrosis in patients with underlying CKD.
  
  METHODS AND RESULTS:
  Human atrial appendage specimens were collected during cardiac surgery from individuals with or without CKD. Cardiac fibrosis was quantified using trichrome staining. For endogenous Klotho functional studies, primary human cardiomyocytes (HCMs) were treated with uremic serum from CKD patients or recombinant human TGF-?1. The effects of endogenous Klotho in HCMs were studied using Klotho-siRNA and Klotho-plasmid transfection. Both gene and protein expression of endogenous Klotho are found in human heart, but decreased Klotho expression is clearly associated with the degree of cardiac fibrosis in CKD patients. Moreover, we show that endogenous Klotho is expressed by HCMs and cardiac fibroblasts (HCFs) but that HCM expression is suppressed by uremic serum or TGF-?1. Klotho knockdown or overexpression aggravates or mitigates TGF-?1-induced fibrosis and canonical Wnt signaling in HCMs, respectively. Furthermore, co-culture of HCMs with HCFs increases TGF-?1-induced fibrogenic proteins in HCFs, but overexpression of endogenous Klotho in HCMs mitigates this effect, suggesting functional crosstalk between HCMs and HCFs.
  
  CONCLUSIONS:
  Our data from analysis of human hearts as well as functional in vitro studies strongly suggests that the loss of cardiac endogenous Klotho in CKD patients, specifically in cardiomyocytes, facilitates intensified TGF-?1 signaling which enables more vigorous cardiac fibrosis through upregulated Wnt signaling. Upregulation of endogenous Klotho inhibits pathogenic Wnt/?-catenin signaling and may offer a novel strategy for prevention and treatment of cardiac fibrosis in CKD patients.
  
  Copyright © 2018. Published by Elsevier Ltd.
  
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• Impact of statins on cellular respiration and de-differentiation of myofibroblasts in human failing hearts.
  ESC Heart Fail

  2019 Sep;():. doi: 10.1002/ehf2.12509.
  
  Emelyanova Larisa, Sra Amar, Schmuck Eric G, Raval Amish N, Downey Francis X, Jahangir Arshad, Rizvi Farhan, Ross Gracious R,
  
  Abstract
  
  AIMS:
  Fibroblast to myofibroblast trans-differentiation with altered bioenergetics precedes cardiac fibrosis (CF). Either prevention of differentiation or promotion of de-differentiation could mitigate CF-related pathologies. We determined whether 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors-statins, commonly prescribed to patients at risk of heart failure (HF)-can de-differentiate myofibroblasts, alter cellular bioenergetics, and impact the human ventricular fibroblasts (hVFs) in HF patients.
  
  METHODS AND RESULTS:
  Either in vitro statin treatment of differentiated myofibroblasts (n = 3-6) or hVFs, isolated from human HF patients under statin therapy (HF + statin) vs. without statins (HF) were randomly used (n = 4-12). In vitro, hVFs were differentiated by transforming growth factor-?1 (TGF-?1) for 72 h (TGF-72 h). Differentiation status and cellular oxygen consumption rate (OCR) were determined by ?-smooth muscle actin (?-SMA) expression and Seahorse assay, respectively. Data are mean ± SEM except Seahorse (mean ± SD); P < 0.05, considered significant. In vitro, statins concentration-dependently de-differentiated the myofibroblasts. The respective half-maximal effective concentrations were 729 ± 13 nmol/L (atorvastatin), 3.6 ± 1 ?mol/L (rosuvastatin), and 185 ± 13 nmol/L (simvastatin). Mevalonic acid (300 ?mol/L), the reduced product of HMG-CoA, prevented the statin-induced de-differentiation (?-SMA expression: 31.4 ± 10% vs. 58.6 ± 12%). Geranylgeranyl pyrophosphate (GGPP, 20 ?mol/L), a cholesterol synthesis-independent HMG-CoA reductase pathway intermediate, completely prevented the statin-induced de-differentiation (?-SMA/GAPDH ratios: 0.89 ± 0.05 [TGF-72 h + 72 h], 0.63 ± 0.02 [TGF-72 h + simvastatin], and 1.2 ± 0.08 [TGF-72 h + simvastatin + GGPP]). Cellular metabolism involvement was observed when co-incubation of simvastatin (200 nmol/L) with glibenclamide (10 ?mol/L), a K channel inhibitor, attenuated the simvastatin-induced de-differentiation (0.84 ± 0.05). Direct inhibition of mitochondrial respiration by oligomycin (1 ng/mL) also produced a de-differentiation effect (0.33 ± 0.02). OCR (pmol O /min/?g protein) was significantly decreased in the simvastatin-treated hVFs, including basal (P = 0.002), ATP-linked (P = 0.01), proton leak-linked (P = 0.01), and maximal (P < 0.001). The OCR inhibition was prevented by GGPP (basal OCR [P = 0.02], spare capacity OCR [P = 0.008], and maximal OCR [P = 0.003]). Congruently, hVFs from HF showed an increased population of myofibroblasts while HF + statin group showed significantly reduced cellular respiration (basal OCR [P = 0.021], ATP-linked OCR [P = 0.047], maximal OCR [P = 0.02], and spare capacity OCR [P = 0.025]) and myofibroblast differentiation (?-SMA/GAPDH: 1 ± 0.19 vs. 0.23 ± 0.06, P = 0.01).
  
  CONCLUSIONS:
  This study demonstrates the de-differentiating effect of statins, the underlying GGPP sensitivity, reduced OCR with potential activation of K channels, and their impact on the differentiation magnitude of hVFs in HF patients. This novel pleiotropic effect of statins may be exploited to reduce excessive CF in patients at risk of HF.
  
  © 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.
  
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• Rapid, proteomic urine assay for monitoring progressive organ disease in Fabry disease.
  J Med Genet

  2019 Sep;():. doi: jmedgenet-2019-106030.
  
  Doykov Ivan D, Heywood Wendy E, Nikolaenko Valeria, ?piewak Justyna, Hällqvist Jenny, Clayton Peter Theodore, Mills Philippa, Warnock David G, Nowak Albina, Mills Kevin,
  
  Abstract
  
  BACKGROUND:
  Fabry disease is a progressive multisystemic disease, which affects the kidney and cardiovascular systems. Various treatments exist but decisions on how and when to treat are contentious. The current marker for monitoring treatment is plasma globotriaosylsphingosine (lyso-Gb3), but it is not informative about the underlying and developing disease pathology.
  
  METHODS:
  We have created a urine proteomic assay containing a panel of biomarkers designed to measure disease-related pathology which include the inflammatory system, lysosome, heart, kidney, endothelium and cardiovascular system. Using a targeted proteomic-based approach, a series of 40 proteins for organ systems affected in Fabry disease were multiplexed into a single 10?min multiple reaction monitoring Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) assay and using only 1?mL of urine.
  
  RESULTS:
  Six urinary proteins were elevated in the early-stage/asymptomatic Fabry group compared with controls including albumin, uromodulin, ?1-antitrypsin, glycogen phosphorylase brain form, endothelial protein receptor C and intracellular adhesion molecule 1. Albumin demonstrated an increase in urine and could indicate presymptomatic disease. The only protein elevated in the early-stage/asymptomatic patients that continued to increase with progressive multiorgan involvement was glycogen phosphorylase brain form. Podocalyxin, fibroblast growth factor 23, cubulin and Alpha-1-Microglobulin/Bikunin Precursor (AMBP) were elevated only in disease groups involving kidney disease. Nephrin, a podocyte-specific protein, was elevated in all symptomatic groups. Prosaposin was increased in all symptomatic groups and showed greater specificity (p<0.025-0.0002) according to disease severity.
  
  CONCLUSION:
  This work indicates that protein biomarkers could be helpful and used in conjunction with plasma lyso-Gb3 for monitoring of therapy or disease progression in patients with Fabry disease.
  
  © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
  
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• Effects of nitric oxide on apoptosis and voltage-gated calcium channels in human cardiac myofibroblasts.
  Clin Exp Pharmacol Physiol

  2019 Sep;():. doi: 10.1111/1440-1681.13178.
  
  Bae Hyemi, Taeho Kim, Lim Inja,
  
  Abstract
  
  We characterised the voltage-gated Ca channels (VGCCs) in human cardiac fibroblasts (HCFs) and myofibroblasts (HCMFs) and investigated the effects of nitric oxide (NO) on apoptosis and on these channels. Western blotting and immunofluorescence analyses show that ?-smooth muscle actin (a myofibroblast marker) was markedly expressed in passage (P) 12-15 but not in P4 HCF cells, whereas calponin (a fibroblast marker) was expressed only in P4 cells. Ca 1.2 (L-type) and Ca 3.3 (T-type) of VGCCs were highly expressed in P12-15 cells, but only weak Ca 2.3 (R-type) expression was identified in P4 cells using reverse transcription-polymerase chain reaction analysis. S-Nitroso-N-acetylpenicillamine (SNAP, an NO donor) decreased cell viability of HCMFs in a dose-dependent manner and induced apoptotic changes, and nifedipine (an L-type Ca channel blocker) prevented apoptosis as shown with immunofluorescence staining and flow cytometry. Whole-cell mode patch clamp recordings demonstrate the presence of L-type Ca (I ) and T-type Ca (I ) currents in HCMFs. SNAP inhibited I of HCMFs, but pre-treatment with ODQ (a guanylate cyclase inhibitor) or KT5823 (a PKG inhibitor) prevented it. Pre-treating cells with KT5720 (a PKA inhibitor) or SQ22536 (an adenylate cyclase inhibitor) blocked SNAP-induced inhibition of I . 8-Bromo-cyclic GMP or 8-bromo-cyclic AMP also inhibited I . However, pre-treatment with N-ethylmaleimide (a thiol-alkylating reagent) did not block the SNAP effect, nor did DL-dithiothreitol (a reducing agent) reverse it. These data suggest that high concentrations of NO injure HCMFs and inhibit I through the PKG and PKA signalling pathways but not through the S-nitrosylation pathway.
  
  © 2019 John Wiley & Sons Australia, Ltd.
  
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• Geleophysic dysplasia: novel missense variants and insights into ADAMTSL2 intracellular trafficking.
  Mol Genet Metab Rep

  2019 Dec;21():100504. doi: 10.1016/j.ymgmr.2019.100504.
  
  Piccolo Pasquale, Sabatino Valeria, Mithbaokar Pratibha, Polishchuck Elena, Law Simon K, Magraner-Pardo Lorena, Pons Tirso, Polishchuck Roman, Brunetti-Pierri Nicola,
  
  Abstract
  
  Geleophysic dysplasia (GPHYSD1, MIM231050; GPHYSD2, MIM614185; GPHYSD3, MIM617809) is an autosomal disorder characterized by short-limb dwarfism, brachydactyly, cardiac valvular disease, and laryngotracheal stenosis. Mutations in , , and genes are responsible for this condition. We found that three previously described cases of GPHYSD diagnosed clinically were homozygote or compound heterozygotes for five variants, four of which not being previously reported. By electron microscopy, skin fibroblasts available in one case homozygote for an variant showed a defective intracellular localization of mutant ADAMTSL2 protein that did not accumulate within lysosome-like intra-cytoplasmic inclusions. Moreover, this mutant ADAMTSL2 protein was less secreted in medium and resulted in increased SMAD2 phosphorylation in transfected HEK293 cells.
  
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• ?-Arrestin 2 mediates arginine vasopressin-induced IL-6 induction via the ERK-NF-?B signal pathway in murine hearts.
  Acta Pharmacol Sin

  2019 Sep;():. doi: 10.1038/s41401-019-0292-y.
  
  Sun Shu-Zhen, Cao Hong, Yao Na, Zhao Ling-Ling, Zhu Xiao-Fang, Ni Er-An, Zhu Qi, Zhu Wei-Zhong,
  
  Abstract
  
  Evidence to date suggests that ?-arrestins act beyond their role as adapter proteins. Arginine vasopressin (AVP) may be a factor in inflammation and fibrosis in the pathogenesis of heart failure. In the present study we investigated the effect of AVP on inflammatory cytokine IL-6 production in murine hearts and the impact of ?-arrestin 2-dependent signaling on AVP-induced IL-6 production. We found that administration of AVP (0.5?U/kg, iv) markedly increased the levels of IL-6 mRNA in rat hearts with the maximum level occurred at 6?h. In ?-arrestin 2 KO mouse hearts, deletion of ?-arrestin 2 decreased AVP-induced IL-6 mRNA expression. We then performed in vitro experiments in adult rat cardiac fibroblasts (ARCFs). We found that AVP (10-10?M) dose-dependently increased the expression of IL-6 mRNA and protein, activation of NF-?B signaling and ERK phosphorylation, whereas knockdown of ?-arrestin 2 blocked AVP-induced IL-6 increase, NF-?B activation and ERK phosphorylation. Pharmacological blockade of ERK using PD98059 diminished AVP-induced NF-?B activation and IL-6 production. The selective V receptor antagonist SR49059 effectively blocked AVP-induced NF-?B phosphorylation and activation as well as IL-6 expression in ARCFs. In AVP-treated mice, pre-injection of SR49059 (2?mg/kg, iv) abolished AVP-induced NF-?B activation and IL-6 production in hearts. The above results suggest that AVP induces IL-6 induction in murine hearts via the V receptor-mediated ?-arrestin2/ERK/NF-?B pathway, thus reveal a novel mechanism of myocardial inflammation in heart failure involving the V/?-arrestin 2/ERK/NF-?B signaling pathway.
  
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• Cell cycle regulators control mesoderm specification in human pluripotent stem cells.
  J Biol Chem

  2019 Sep;():. doi: jbc.RA119.008251.
  
  Yiangou Loukia, Grandy Rodrigo A, Osnato Anna, Ortmann Daniel, Sinha Sanjay, Vallier Ludovic,
  
  Abstract
  
  The mesoderm is one of the three germ layers produced during gastrulation from which muscle, bones, kidneys, and the cardiovascular system originate. Understanding the mechanisms that control mesoderm specification could inform many applications, including the development of regenerative medicine therapies to manage diseases affecting these tissues. Here, we used human pluripotent stem cells (hPSCs) to investigate the role of cell cycle in mesoderm formation. To this end, using small molecules or conditional gene knockdown, we inhibited proteins controlling G1 and G2/M cell cycle phases during the differentiation of hPSCs into lateral plate, cardiac, and presomitic mesoderm. These loss-of-function experiments revealed that regulators of the G1 phase such as cyclin-dependent kinases (CDKs) and phosphorylation of retinoblastoma protein (pRb) are necessary for efficient mesoderm formation in a context-dependent manner. Further investigations disclosed that inhibition of the G2/M regulator CDK1 decreases bone morphogenetic protein (BMP) signaling activity specifically during lateral plate mesoderm formation while reducing fibroblast growth factor (FGF)/extracellular signaling-regulated kinase 1/2 (ERK1/2) activity in all mesoderm subtypes. Taken together, our findings reveal that cell cycle regulators direct mesoderm formation by controlling the activity of key developmental pathways.
  
  Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
  
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• Doxorubicin induces trans-differentiation and MMP1 expression in cardiac fibroblasts via cell death-independent pathways.
  PLoS One

  2019 ;14(9):e0221940. doi: 10.1371/journal.pone.0221940.
  
  Narikawa Masatoshi, Umemura Masanari, Tanaka Ryo, Hikichi Mayu, Nagasako Akane, Fujita Takayuki, Yokoyama Utako, Ishigami Tomoaki, Kimura Kazuo, Tamura Kouichi, Ishikawa Yoshihiro,
  
  Abstract
  
  Although doxorubicin (DOX)-induced cardiomyopathy causes lethal heart failure (HF), no early detection or effective treatment methods are available. The principal mechanisms of cardiotoxicity are considered to involve oxidative stress and apoptosis of cardiomyocytes. However, the effect of DOX on cardiac fibroblasts at non-lethal concentrations remains unknown. The aim of this study was to investigate the direct effect of doxorubicin on the activation of cardiac fibroblasts independent of cell death pathways. We first found that DOX induced ?-SMA expression (marker of trans-differentiation) at a low concentration range, which did not inhibit cell viability. DOX also increased MMP1, IL-6, TGF-? and collagen expression in human cardiac fibroblasts (HCFs). In addition, DOX promoted Akt and Smad phosphorylation. A Smad inhibitor prevented DOX-induced ?-SMA and IL-6 protein expression. An PI3K inhibitor also prevented MMP1 mRNA expression in HCFs. These findings suggest that DOX directly induces fibrotic changes in HCFs via cell death-independent pathways. Furthermore, we confirmed that these responses are organ- and species-specific for HCFs based on experiments using different types of human and murine fibroblast cell lines. These results suggest potentially new mechanisms of DOX-induced cardiotoxicity from the viewpoint of fibrotic changes in cardiac fibroblasts.
  
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• Novel synonymous and missense variants in FGFR1 causing Hartsfield syndrome.
  Am J Med Genet A

  2019 Sep;():. doi: 10.1002/ajmg.a.61354.
  
  Courage Carolina, Jackson Christopher B, Owczarek-Lipska Marta, Jamsheer Aleksander, Sowi?ska-Seidler Anna, Piotrowicz Ma?gorzata, Jakubowski Lucjusz, Dallèves Fanny, Riesch Erik, Neidhardt John, Lemke Johannes R,
  
  Abstract
  
  Hartsfield syndrome is a rare clinical entity characterized by holoprosencephaly and ectrodactyly with the variable feature of cleft lip/palate. In addition to these symptoms patients with Hartsfield syndrome can show developmental delay of variable severity, isolated hypogonadotropic hypogonadism, central diabetes insipidus, vertebral anomalies, eye anomalies, and cardiac malformations. Pathogenic variants in FGFR1 have been described to cause phenotypically different FGFR1-related disorders such as Hartsfield syndrome, hypogonadotropic hypogonadism with or without anosmia, Jackson-Weiss syndrome, osteoglophonic dysplasia, Pfeiffer syndrome, and trigonocephaly Type 1. Here, we report three patients with Hartsfield syndrome from two unrelated families. Exome sequencing revealed two siblings harboring a novel de novo heterozygous synonymous variant c.1029G>A, p.Ala343Ala causing a cryptic splice donor site in exon 8 of FGFR1 likely due to gonadal mosaicism in one parent. The third case was a sporadic patient with a novel de novo heterozygous missense variant c.1868A>G, p.(Asp623Gly).
  
  © 2019 Wiley Periodicals, Inc.
  
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• Anti-fibrotic effects of curcumin and some of its analogues in the heart.
  Heart Fail Rev

  2019 Sep;():. doi: 10.1007/s10741-019-09854-6.
  
  Gorabi Armita Mahdavi, Hajighasemi Saeideh, Kiaie Nasim, Rosano Giuseppe M C, Sathyapalan Thozhukat, Al-Rasadi Khalid, Sahebkar Amirhossein,
  
  Abstract
  
  Cardiac fibrosis stems from the changes in the expression of fibrotic genes in cardiac fibroblasts (CFs) in response to the tissue damage induced by various cardiovascular diseases (CVDs) leading to their transformation into active myofibroblasts, which produce high amounts of extracellular matrix (ECM) proteins leading, in turn, to excessive deposition of ECM in cardiac tissue. The excessive accumulation of ECM elements causes heart stiffness, tissue scarring, electrical conduction disruption and finally cardiac dysfunction and heart failure. Curcumin (Cur; also known as diferuloylmethane) is a polyphenol compound extracted from rhizomes of Curcuma longa with an influence on an extensive spectrum of biological phenomena including cell proliferation, differentiation, inflammation, pathogenesis, chemoprevention, apoptosis, angiogenesis and cardiac pathological changes. Cumulative evidence has suggested a beneficial role for Cur in improving disrupted cardiac function developed by cardiac fibrosis by establishing a balance between degradation and synthesis of ECM components. There are various molecular mechanisms contributing to the development of cardiac fibrosis. We presented a review of Cur effects on cardiac fibrosis and the discovered underlying mechanisms by them Cur interact to establish its cardio-protective effects.
  
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• Targeting cardiac fibrosis with engineered T cells.
  Nature

  2019 Sep;():. doi: 10.1038/s41586-019-1546-z.
  
  Aghajanian Haig, Kimura Toru, Rurik Joel G, Hancock Aidan S, Leibowitz Michael S, Li Li, Scholler John, Monslow James, Lo Albert, Han Wei, Wang Tao, Bedi Kenneth, Morley Michael P, Linares Saldana Ricardo A, Bolar Nikhita A, McDaid Kendra, Assenmacher Charles-Antoine, Smith Cheryl L, Wirth Dagmar, June Carl H, Margulies Kenneth B, Jain Rajan, Puré Ellen, Albelda Steven M, Epstein Jonathan A,
  
  Abstract
  
  Fibrosis is observed in nearly every form of myocardial disease. Upon injury, cardiac fibroblasts in the heart begin to remodel the myocardium by depositing excess extracellular matrix, resulting in increased stiffness and reduced compliance of the tissue. Excessive cardiac fibrosis is an important factor in the progression of various forms of cardiac disease and heart failure. However, clinical interventions and therapies that target fibrosis remain limited. Here we demonstrate the efficacy of redirected T cell immunotherapy to specifically target pathological cardiac fibrosis in mice. We find that cardiac fibroblasts that express a xenogeneic antigen can be effectively targeted and ablated by adoptive transfer of antigen-specific CD8 T cells. Through expression analysis of the gene signatures of cardiac fibroblasts obtained from healthy and diseased human hearts, we identify an endogenous target of cardiac fibroblasts-fibroblast activation protein. Adoptive transfer of T cells that express a chimeric antigen receptor against fibroblast activation protein results in a significant reduction in cardiac fibrosis and restoration of function after injury in mice. These results provide proof-of-principle for the development of immunotherapeutic drugs for the treatment of cardiac disease.
  
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• Transcatheter aortic valve replacements alter circulating serum factors to mediate myofibroblast deactivation.
  Sci Transl Med

  2019 Sep;11(509):. doi: eaav3233.
  
  Aguado Brian A, Schuetze Katherine B, Grim Joseph C, Walker Cierra J, Cox Anne C, Ceccato Tova L, Tan Aik-Choon, Sucharov Carmen C, Leinwand Leslie A, Taylor Matthew R G, McKinsey Timothy A, Anseth Kristi S,
  
  Abstract
  
  The transcatheter aortic valve replacement (TAVR) procedure has emerged as a minimally invasive treatment for patients with aortic valve stenosis (AVS). However, alterations in serum factor composition and biological activity after TAVR remain unknown. Here, we quantified the systemic inflammatory effects of the TAVR procedure and hypothesized that alterations in serum factor composition would modulate valve and cardiac fibrosis. Serum samples were obtained from patients with AVS immediately before their TAVR procedure (pre-TAVR) and about 1 month afterward (post-TAVR). Aptamer-based proteomic profiling revealed alterations in post-TAVR serum composition, and ontological analysis identified inflammatory macrophage factors implicated in myofibroblast activation and deactivation. Hydrogel biomaterials used as valve matrix mimics demonstrated that post-TAVR serum reduced myofibroblast activation of valvular interstitial cells relative to pre-TAVR serum from the same patient. Transcriptomics and curated network analysis revealed a shift in myofibroblast phenotype from pre-TAVR to post-TAVR and identified p38 MAPK signaling as one pathway involved in pre-TAVR-mediated myofibroblast activation. Post-TAVR serum deactivated valve and cardiac myofibroblasts initially exposed to pre-TAVR serum to a quiescent fibroblast phenotype. Our in vitro deactivation data correlated with patient disease severity measured via echocardiography and multimorbidity scores, and correlations were dependent on hydrogel stiffness. Sex differences in cellular responses to male and female sera were also observed and may corroborate clinical observations regarding sex-specific TAVR outcomes. Together, alterations in serum composition after TAVR may lead to an antifibrotic fibroblast phenotype, which suggests earlier interventions may be beneficial for patients with advanced AVS to prevent further disease progression.
  
  Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
  
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• ?Klotho Regulates Age-Associated Vascular Calcification and Lifespan in Zebrafish.
  Cell Rep

  2019 Sep;28(11):2767-2776.e5. doi: S2211-1247(19)31046-0.
  
  Singh Ajeet Pratap, Sosa Maria X, Fang Jian, Shanmukhappa Shiva Kumar, Hubaud Alexis, Fawcett Caroline H, Molind Gregory J, Tsai Tingwei, Capodieci Paola, Wetzel Kristie, Sanchez Ellen, Wang Guangliang, Coble Matthew, Tang Wenlong, Cadena Samuel M, Fishman Mark C, Glass David J,
  
  Abstract
  
  The hormone ?Klotho regulates lifespan in mice, as knockouts die early of what appears to be accelerated aging due to hyperphosphatemia and soft tissue calcification. In contrast, the overexpression of ?Klotho increases lifespan. Given the severe mouse phenotype, we generated zebrafish mutants for ?klotho as well as its binding partner fibroblast growth factor-23 (fgf23). Both mutations cause shortened lifespan in zebrafish, with abrupt onset of behavioral and degenerative physical changes at around 5 months of age. There is a calcification of vessels throughout the body, most dramatically in the outflow tract of the heart, the bulbus arteriosus (BA). This calcification is associated with an ectopic activation of osteoclast differentiation pathways. These findings suggest that the gradual loss of ?Klotho found in normal aging might give rise to ectopic calcification.
  
  Copyright © 2019 Novartis Institutes for Biomedical Research. Published by Elsevier Inc. All rights reserved.
  
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• Discovery of Retinoic Acid Receptor Agonists as Proliferators of Cardiac Progenitor Cells Through a Phenotypic Screening Approach.
  Stem Cells Transl Med

  2019 Sep;():. doi: 10.1002/sctm.19-0069.
  
  Drowley Lauren, McPheat Jane, Nordqvist Anneli, Peel Samantha, Karlsson Ulla, Martinsson Sofia, Müllers Erik, Dellsén Anita, Knight Sinead, Barrett Ian, Sánchez José, Magnusson Björn, Greber Boris, Wang Qing-Dong, Plowright Alleyn T,
  
  Abstract
  
  Identification of small molecules with the potential to selectively proliferate cardiac progenitor cells (CPCs) will aid our understanding of the signaling pathways and mechanisms involved and could ultimately provide tools for regenerative therapies for the treatment of post-MI cardiac dysfunction. We have used an in vitro human induced pluripotent stem cell-derived CPC model to screen a 10,000-compound library containing molecules representing different target classes and compounds reported to modulate the phenotype of stem or primary cells. The primary readout of this phenotypic screen was proliferation as measured by nuclear count. We identified retinoic acid receptor (RAR) agonists as potent proliferators of CPCs. The CPCs retained their progenitor phenotype following proliferation and the identified RAR agonists did not proliferate human cardiac fibroblasts, the major cell type in the heart. In addition, the RAR agonists were able to proliferate an independent source of CPCs, HuES6. The RAR agonists had a time-of-differentiation-dependent effect on the HuES6-derived CPCs. At 4?days of differentiation, treatment with retinoic acid induced differentiation of the CPCs to atrial cells. However, after 5?days of differentiation treatment with RAR agonists led to an inhibition of terminal differentiation to cardiomyocytes and enhanced the proliferation of the cells. RAR agonists, at least transiently, enhance the proliferation of human CPCs, at the expense of terminal cardiac differentiation. How this mechanism translates in vivo to activate endogenous CPCs and whether enhancing proliferation of these rare progenitor cells is sufficient to enhance cardiac repair remains to be investigated. Stem Cells Translational Medicine2019.
  
  © 2019 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.
  
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• Phenotypic Plasticity of Fibroblasts during Mammary Carcinoma Development.
  Int J Mol Sci

  2019 Sep;20(18):. doi: E4438.
  
  Elwakeel Eiman, Brüggemann Mirko, Fink Annika F, Schulz Marcel H, Schmid Tobias, Savai Rajkumar, Brüne Bernhard, Zarnack Kathi, Weigert Andreas,
  
  Abstract
  
  Cancer-associated fibroblasts (CAFs) in the tumor microenvironment contribute to all stages of tumorigenesis and are usually considered to be tumor-promoting cells. CAFs show a remarkable degree of heterogeneity, which is attributed to developmental origin or to local environmental niches, resulting in distinct CAF subsets within individual tumors. While CAF heterogeneity is frequently investigated in late-stage tumors, data on longitudinal CAF development in tumors are lacking. To this end, we used the transgenic polyoma middle T oncogene-induced mouse mammary carcinoma model and performed whole transcriptome analysis in FACS-sorted fibroblasts from early- and late-stage tumors. We observed a shift in fibroblast populations over time towards a subset previously shown to negatively correlate with patient survival, which was confirmed by multispectral immunofluorescence analysis. Moreover, we identified a transcriptomic signature distinguishing CAFs from early- and late-stage tumors. Importantly, the signature of early-stage CAFs correlated well with tumor stage and survival in human mammary carcinoma patients. A random forest analysis suggested predictive value of the complete set of differentially expressed genes between early- and late-stage CAFs on bulk tumor patient samples, supporting the clinical relevance of our findings. In conclusion, our data show transcriptome alterations in CAFs during tumorigenesis in the mammary gland, which suggest that CAFs are educated by the tumor over time to promote tumor development. Moreover, we show that murine CAF gene signatures can harbor predictive value for human cancer.
  
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• Dietary vitamin D interacts with high phosphate-induced cardiac remodeling in rats with normal renal function.
  Nephrol Dial Transplant

  2019 Aug;():. doi: gfz156.
  
  Hu Ming Chang, Scanni Roberto, Ye Jianfeng, Zhang Jianning, Shi Mingjun, Maique Jenny, Flores Brianna, Moe Orson W, Krapf Reto,
  
  Abstract
  
  BACKGROUND:
  Vitamin D (VD) and phosphate (Pi) load are considered as contributors to cardiovascular disease in chronic kidney disease and the general population, but interactive effects of VD and Pi intake on the heart are not clearly illustrated.
  
  METHODS:
  We fed normal male rats with three levels of dietary VD (100, 1100 or 5000 IU/kg chow) and Pi (0.2, 0.6 or 1.6%) (3X3 design) for 8 weeks and examined renal and cardiac function and histology.
  
  RESULTS:
  High dietary Pi decreased plasma and renal Klotho and plasma 25-hydroxyvitamin D, and increased plasma Pi, fibroblast growth factor 23 and parathyroid hormone without affecting renal function, while low Pi increased plasma and renal Klotho. Both low and high VD diets enhanced high Pi-reduced Klotho expression. Low dietary VD reduced-plasma Klotho was rescued by a low Pi diet. High dietary Pi reduced-cardiac ejection fraction was not modified by a low or high VD diet, but the dietary VD effects on cardiac pathologic changes were more complex. High dietary Pi-induced cardiac hypertrophy was attenuated by a low VD and exacerbated by a high VD diet. In contrast, high dietary Pi -induced cardiac fibrosis was magnified by a low VD and attenuated by a high VD diet.
  
  CONCLUSIONS:
  High Pi diet induces hypertrophy and fibrosis in left ventricles, a low VD diet accelerates high Pi-induced fibrosis, and a high VD diet exacerbated high Pi -induced hypertrophy. Therefore, cardiac phosphotoxicity is exacerbated by either high or low dietary VD in rats with normal kidney function.
  
  © The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
  
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• ADAPT-treated pericardium for aortic valve reconstruction in congenital heart disease: histological analysis of a series of human explants.
  Eur J Cardiothorac Surg

  2019 Aug;():. doi: ezz228.
  
  Nordmeyer Sarah, Kretzschmar Johanna, Murin Peter, Cho Mi-Young, Foth Rudi, Schlichting Uwe, Berger Felix, Ovroutski Stanislav, Photiadis Joachim, Sigler Matthias,
  
  Abstract
  
  OBJECTIVES:
  Different types of patch materials are used for aortic valve repair in children with congenital aortic valve disease to avoid early valve replacement. CardioCel© (Admedus, Toowong, QLD, Australia) consists of bovine pericardium treated with the ADAPT method (Admedus' proprietary tissue engineering process).
  
  METHODS:
  Our goal was to describe tissue reactions in 12 explanted aortic valve leaflet specimens (augmented or replaced with CardioCel patch material) (11 explanted surgically, 1 autopsy). Explantation was performed during reoperation after aortic valve repair, necessitated by aortic valve stenosis in 5, aortic valve insufficiency in 2, combined aortic valve lesions in 3 patients and endocarditis in 1 patient. One patient died of sudden left heart failure 28?months after aortic valve repair. At the last documented follow-up of this patient at 22?months, he showed mild aortic valve stenosis and insufficiency. Implantation time (time between implantation and explantation) of CardioCel patches was a median of 25 (range 11-47) months. Explants were examined using a uniform protocol with methylmethacrylate and/or paraffin embedding after fixation in formalin. Besides standard histological staining, von Kossa (for identification of calcifications) and immunohistochemical stains were applied with antibodies specific for muscular, inflammatory and connective tissue component antigens. Findings regarding the extent of appositional growth on top of the patch consisting of fibroblasts and extracellular matrix components, calcification, and inflammation were rated using a 4-grade scale (G0 no/G1 few/G2 moderate/G3 massive).
  
  RESULTS:
  Superficial endothelialization was demonstrated in all patients by immunohistochemical analysis. Nine specimens showed mild inflammatory cell infiltration (G1) (G2: n?=?3). Significant appositional growth on top of the patch due to addition of fibroblasts and extracellular matrix components, was seen in all specimens (G1: n?=?1; G2: n?=?7; G3: n?=?4). Ten of 12 samples with implant times of 23?months or longer revealed calcifications (G1: n?=?6; G2: n?=?3; G3: n?=?1). Two specimens with the shortest implant times (11 and 20?months) showed no calcifications (G0). Thrombus apposition with granulocyte infiltration was demonstrated in the specimen of the patient with endocarditis.
  
  CONCLUSIONS:
  In our cohort, all CardioCel patches used for aortic valve repair in patients with congenital heart disease demonstrated appositional growth of fibroblasts and extracellular matrix components, and calcification after an implant time of at least 23?months.
  
  © The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
  
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• Novel technique for the simultaneous isolation of cardiac fibroblasts and epicardial stromal cells from the infarcted murine heart.
  Cardiovasc Res

  2019 Aug;():. doi: cvz193.
  
  Owenier Christoph, Hesse Julia, Alter Christina, Ding Zhaoping, Marzoq Aseel, Petzsch Patrick, Köhrer Karl, Schrader Jürgen,
  
  Abstract
  
  AIMS:
  Myocardial infarction (MI) leads to activation of cardiac fibroblasts (aCFs) and at the same time induces the formation of epicardium-derived cells at the heart surface. To discriminate between the two cell populations, we elaborated a fast and efficient protocol for the simultaneous isolation and characterization of aCFs and epicardial stromal cells (EpiSCs) from the infarcted mouse heart.
  
  METHODS AND RESULTS:
  For the isolation of aCFs and EpiSCs, infarcted hearts (50?min ischaemia/reperfusion) were digested by perfusion with a collagenase-containing medium for only 8?min, while EpiSCs were enzymatically removed from the outside by applying mild shear forces via a motor driven device. Cardiac fibroblasts (CFs) isolated from unstressed hearts served as control. Viability of isolated cells was >90%. Purity of EpiSCs was confirmed by immunofluorescence staining and qPCR of various mesenchymal markers including Wilms-tumor-protein-1. Microarray analysis of CFs, aCFs, and EpiSCs on day 5 post-MI revealed a unique gene expression pattern in the EpiSC fraction, which was enriched for epithelial markers and epithelial to mesenchymal transition-related genes. Compared to aCFs, 336 significantly altered gene entities were identified in the EpiSC fraction. qPCR analysis showed high expression of Serpinb2, Cxcl13, Adora2b, and Il10 in EpiSCs relative to CFs and aCFs. Furthermore, microarray data identified Ddah1 and Cemip to be highly up-regulated in aCFs compared to CFs. Immunostaining of the infarcted heart revealed a unique distribution of Dermokine, Aquaporin-1, Cytokeratin, Lipocalin2, and Periostin within the epicardial cell layer.
  
  CONCLUSIONS:
  We describe the simultaneous isolation of viable, purified fractions of aCFs and EpiSCs from the infarcted mouse heart. In this study, several differentially expressed markers for aCFs and EpiSCs were identified, underlining the importance of cell separation to study heterogeneity of stromal cells in the healing process after MI.
  
  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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