Pubblicazioni recenti - cardiac fibrosis

• Adenosine A receptor activation prevents DOCA-salt induced hypertensive cardiac remodeling via iBAT.
  Biochem Biophys Res Commun

  2020 Feb;():. doi: S0006-291X(20)30301-6.
  
  Zhou Yan-Ping, Ruan Cheng-Chao, Kong Ling-Ran, Gao Ping-Jin,
  
  Abstract
  
  Hypertensive cardiac remodeling is a constellation of abnormalities that includes cardiomyocyte hypertrophy and death and tissue fibrosis. Adenosine is a long-known vasodilator, through interacting with its four cell surface receptor subtypes in cardiovascular system. However, it is unclear that whether adenosine A receptor (AR) activation is involved in the cardiac remodeling in hypertension. WT mice were utilized to induce DOCA-salt sensitive hypertension and received AR agonist CGS21680 or antagonist KW6002 treatment. Cardiac functional phenotyping measurement by echocardiography showed that CGS21680 improved cardiac dysfunction in DOCA-salt mice. Moreover, CGS21680 reduced cardiomyocyte hypertrophy, cardiac inflammation and fibrosis. However, iBAT depletion surgery induces dramatic cardiac remodeling in DOCA-salt mice, and the protective function of CGS21680 was blocked without intact iBAT. Mechanistically, AR agonist CGS21680 increased iBAT-derived fibroblast growth factor 21 (FGF21). Our data suggest that activation of AR could be a potential therapeutic strategy in preventing heart damage in hypertension.
  
  Copyright © 2020 Elsevier Inc. All rights reserved.
  
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• HUANGKUISIWUFANG inhibits pyruvate dehydrogenase to improve glomerular injury in anti-Thy1 nephritis model.
  J Ethnopharmacol

  2020 Feb;():. doi: S0378-8741(19)32025-2.
  
  Lu Ting, Bian Yong, Zhu Yan, Guo Mengjie, Yang Ye, Guo Jianming, Gu Chunyan, Duan Jin-Ao,
  
  Abstract
  
  ETHNOPHARMACOLOGICAL RELEVANCE:
  Huangkuisiwufang (HKSWF) is composed of Abelmoschus manihot (L.) Medik., Astragalus mongholicus, Polygonum cuspidatum, Curcuma longa L.. Abelmoschus Manihot (L.) Medik. has been widely used for the treatment of chronic renal disease, oral ulcers and burn in China for centuries (Committee of the Pharmacopoeia of PR China, 2010). Abelmoschus manihot (L.) Medik., Polygonum cuspidatum, Curcuma longa L. have been mainly applied in folk medicine for their therapeutic effects on diabetes, cancer, heart disease and other diseases.
  
  AIM OF THE STUDY:
  We aimed to investigate the renoprotective function of HKSWF in anti-Thy nephritis model and clarify the relevant mechanisms.
  
  MATERIALS AND METHODS:
  One week after the model of glomerulonephritis created by injecting anti-thymocyte serum (ATS), rats were treated with Huangkui capsule, enalapril or HKSWF by gavage for a period of 8 weeks. The therapeutic effect was evaluated by detection of proteinuria, plasma creatine, blood urea nitrogen (BUN), podocyte injury, glomerular accumulation of extracellular matrix (ECM) and the markers of oxidative stress and renal fibrosis. RNA Sequencing (RNA-seq), KEGG and western blotting analysis were performed to indicate the signaling pathway involved in the therapeutic effect of HKSWF.
  
  RESULTS:
  Nephritic rats presented the increase of BUN, serum creatinine (Scr), proteinuria, podocyte damage, glomerular fibrosis, Ang II type 1 receptor (AT1R), and the reduction of creatinine clearance (Ccr). In contrast, application of HKSWF to nephritic rats decreased the levels of BUN and proteinuria, promoted mesangial cell recovery and improved oxidative stress level and podocyte injury. KEGG analysis revealed that pyruvate metabolism was the most significantly upregulated pathway in rats treated with HKSWF compared to disease control group. Increased pyruvate dehydrogenase and PAI-1 caused by nephritis was inhibited by HKSWF interposition. Furthermore, dichloroacetate sodium (DCA), an agonist of pyruvate dehydrogenase, could stimulate PAI-1 expression, which was suppressed by HKSWF.
  
  CONCLUSION:
  Chinese herbal preparation HKSWF has remarkable curative effects on glomerulonephritis animals. HKSWF attenuates pyruvate dehydrogenase to improve glomerular injury.
  
  Copyright © 2020. Published by Elsevier B.V.
  
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• The Role of Mast Cells in IgE-Independent Lung Diseases.
  Clin Rev Allergy Immunol

  2020 Feb;():. doi: 10.1007/s12016-020-08779-5.
  
  Komi Daniel Elieh Ali, Mortaz Esmaeil, Amani Saeede, Tiotiu Angelica, Folkerts Gert, Adcock Ian M,
  
  Abstract
  
  Mast cells (MCs) are granular cells of the innate immune system which develop from CD34/CD117 progenitors and play a role in orchestrating adaptive immune responses. They have a well-known role in allergic reactions following immunoglobulin (Ig)E-mediated activation of the cell-surface expressed IgE high-affinity receptor (Fc?RI). MCs can also respond to various other stimuli due to the expression of a variety of receptors including toll-like receptors (TLRs), immunoglobulin (IgG) receptors (Fc?R), complement receptors such as C5a (CD88) expressed by skin MCs, neuropeptides receptors including nerve growth factor receptor, (NGFR), cytokines receptors such as (IL)-1R and IL-3R, and chemokines receptors including CCR-1 and CCR-3. MCs release three groups of mediators upon degranulation differentiated according to their chemical composition, storage, and time to release. These include preformed mediators (mainly histamine, tryptase, and chymase), de novo synthesized mediators such as prostaglandin (PG)D2, leukotriene (LT)B4 and LTD4, and cytokines including IL-1?, IL-3, tumor necrosis factor (TNF)?, and transforming growth factor(TGF)-?. Emerging evidence indicates a role for IgE-independent MC activation in the late-stage asthmatic response as well as in non-allergic airway diseases including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and lung cancer. MC infiltration/activation has been reported in some, but not all, studies of lung cancer. MC-derived TNF-? possesses tumor-suppressive activity while IL-1? supports tumor progression and metastasis. In IPF lungs, an increase in density of tryptase- and chymase-positive MCs (MCTC) and overexpression of TGF-? support the fibrosis progression. MC-derived chymase activates latent TGF-? that induces the differentiation of fibroblasts to matrix-producing myofibroblasts. In summary, increasing evidence highlights a critical role of MCs in non-allergic diseases that may indicate new approaches for therapy.
  
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• The planimetric Grothoff's criteria by cardiac magnetic resonance can improve the specificity of left ventricular non-compaction diagnosis in thalassemia intermedia.
  Int J Cardiovasc Imaging

  2020 Feb;():. doi: 10.1007/s10554-020-01797-6.
  
  Macaione Francesca, Meloni Antonella, Positano Vincenzo, Pistoia Laura, Barison Andrea, Di Lisi Daniele, Spasiano Anna, Campisi Saveria, Spiga Alessandra, Righi Riccardo, Novo Giuseppina, Novo Salvatore, Pepe Alessia,
  
  Abstract
  
  We differentiated the left ventricle non-compaction (LVNC) from hypertrabeculated myocardium due to a negative remodeling in thalassemia intermedia (TI) patients applying linear and planimetric criteria and comparing the cardiovascular magnetic resonance (CMR) findings. CMR images were analyzed in 181 TI patients enrolled in the Myocardial Iron Overload in Thalassemia Network and 27 patients with proved LVNC diagnosis. The CMR diagnostic criteria applied in TI patients were: a modified linear CMR Petersen's criterion based on a more restrictive ratio of diastolic NC/C?>?2.5 at segmental level and the combination of planimetric Grothoff's criteria (percentage of trabeculated LV myocardial mass LV-MM???25% of global LV mass and total LV-MMI NC???15 g/m). Seventeen TI patients showed at least one positive NC/C segment. Compared to LVNC patients, these patients showed a lower frequency of segments with non-compaction areas (2.41?±?1.33 vs 5.48?±?2.26; P??2.5 showed morphological and functional CMR parameters significantly different from the patients with a proved diagnosis of LVNC. Differentiation of LVNC from hypertrabeculated LV in ?-TI patients due to a negative heart remodeling depends on the selected CMR criterion. We suggest using planimetric Grothoff's criteria to improve the specificity of LVNC diagnosis.
  
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• Transplantation of human induced pluripotent stem cell-derived cardiomyocytes improves myocardial function and reverses ventricular remodeling in infarcted rat hearts.
  Stem Cell Res Ther

  2020 Feb;11(1):73. doi: 10.1186/s13287-020-01602-0.
  
  Guan Xumin, Xu Wanzi, Zhang He, Wang Qian, Yu Jiuyang, Zhang Ruyi, Chen Yamin, Xia Yunlong, Wang Jiaxian, Wang Dongjin,
  
  Abstract
  
  BACKGROUND:
  Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have shed great light on cardiac regenerative medicine and specifically myocardial repair in heart failure patients. However, the treatment efficacy and the survival of iPSC-CMs in vivo after transplantation have yielded inconsistent results.
  
  OBJECTIVES:
  The objective of this study was to evaluate the ability of human iPSC-CMs to improve myocardial function in a rat postinfarction heart failure model.
  
  METHODS:
  Eight-week-old male Sprague-Dawley rats were randomly selected to receive an intramyocardial injection of 5% albumin solution with or without 1?×?10 human iPSC-CMs 10?days after undergoing left anterior descending (LAD) coronary artery ligation. Cyclosporine A and methylprednisolone were administered before iPSC-CM injection and until the rats were killed to prevent graft rejection. Cardiac function was evaluated by echocardiography. The survival of grafted cardiomyocytes was confirmed by observing the fluorescent cell tracer Vybrant? CM-DiI or expression of the enhanced green fluorescent protein (eGFP) in transplanted cells, or survival was demonstrated by polymerase chain reaction (PCR)-based detection of human mitochondrial DNA. Sirius red stain was used to evaluate the fibrosis ratio. Hematoxylin-eosin staining was used to observe the formation of teratomas.
  
  RESULTS:
  Four weeks after intramyocardial injection of iPSC-CMs, animals undergoing iPSC-CM transplantation had lower mortality than the control group. Animals injected with cell-free solution (control group) demonstrated significant left ventricular (LV) functional deterioration, whereas grafting of iPSC-CMs attenuated this remodeling process. In the control group, the ejection fraction deteriorated by 10.11% (from 46.36 to 41.67%), and fractional shortening deteriorated by 9.23% (from 24.37 to 22.12%) by 4?weeks. In the iPSC-CM injection group, the ejection fraction improved by 18.86% (from 44.09 to 52.41%), and fractional shortening improved by 23.69% (from 23.08 to 28.54%). Cell labeling, tracking, and molecular biology techniques indicated that the grafted cardiomyocytes survived in the rat heart 1 month after iPSC-CM transplantation. Myocardial fibrosis was also attenuated in the iPSC-CM treatment group.
  
  CONCLUSIONS:
  Human iPSC-CM grafts survived in infarcted rat hearts and restored myocardial function 4?weeks after transplantation. Cell replacement therapy also reversed ventricular remodeling, indicating the potential of iPSC-CMs for cardiac repair strategies.
  
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• The ER Unfolded Protein Response Effector, ATF6, Reduces Cardiac Fibrosis and Decreases Activation of Cardiac Fibroblasts.
  Int J Mol Sci

  2020 Feb;21(4):. doi: E1373.
  
  Stauffer Winston T, Blackwood Erik A, Azizi Khalid, Kaufman Randal J, Glembotski Christopher C,
  
  Abstract
  
  Activating transcription factor-6 ? (ATF6) is one of the three main sensors and effectors of the endoplasmic reticulum (ER) stress response and, as such, it is critical for protecting the heart and other tissues from a variety of environmental insults and disease states. In the heart, ATF6 has been shown to protect cardiac myocytes. However, its roles in other cell types in the heart are unknown. Here we show that ATF6 decreases the activation of cardiac fibroblasts in response to the cytokine, transforming growth factor ? (TGF?), which can induce fibroblast trans-differentiation into a myofibroblast phenotype through signaling via the TGF?-Smad pathway. ATF6 activation suppressed fibroblast contraction and the induction of ? smooth muscle actin (?SMA). Conversely, fibroblasts were hyperactivated when ATF6 was silenced or deleted. ATF6 thus represents a novel inhibitor of the TGF?-Smad axis of cardiac fibroblast activation.
  
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• Feasibility of selective cardiac ventricular electroporation.
  PLoS One

  2020 ;15(2):e0229214. doi: 10.1371/journal.pone.0229214.
  
  Sugrue Alan, Vaidya Vaibhav R, Livia Christopher, Padmanabhan Deepak, Abudan Anas, Isath Ameesh, Witt Tyra, DeSimone Christopher V, Stalboerger Paul, Kapa Suraj, Asirvatham Samuel J, McLeod Christopher J,
  
  Abstract
  
  INTRODUCTION:
  The application of brief high voltage electrical pulses to tissue can lead to an irreversible or reversible electroporation effect in a cell-specific manner. In the management of ventricular arrhythmias, the ability to target different tissue types, specifically cardiac conduction tissue (His-Purkinje System) vs. cardiac myocardium would be advantageous. We hypothesize that pulsed electric fields (PEFs) can be applied safely to the beating heart through a catheter-based approach, and we tested whether the superficial Purkinje cells can be targeted with PEFs without injury to underlying myocardial tissue.
  
  METHODS:
  In an acute (n = 5) and chronic canine model (n = 6), detailed electroanatomical mapping of the left ventricle identified electrical signals from myocardial and overlying Purkinje tissue. Electroporation was effected via percutaneous catheter-based Intracardiac bipolar current delivery in the anesthetized animal. Repeat Intracardiac electrical mapping of the heart was performed at acute and chronic time points; followed by histological analysis to assess effects.
  
  RESULTS:
  PEF demonstrated an acute dose-dependent functional effect on Purkinje, with titration of pulse duration and/or voltage associated with successful acute Purkinje damage. Electrical conduction in the insulated bundle of His (n = 2) and anterior fascicle bundle (n = 2), was not affected. At 30 days repeat cardiac mapping demonstrated resilient, normal electrical conduction throughout the targeted area with no significant change in myocardial amplitude (pre 5.9 ± 1.8 mV, 30 days 5.4 ± 1.2 mV, p = 0.92). Histopathological analysis confirmed acute Purkinje fiber targeting, with chronic studies showing normal Purkinje fibers, with minimal subendocardial myocardial fibrosis.
  
  CONCLUSION:
  PEF provides a novel, safe method for non-thermal acute modulation of the Purkinje fibers without significant injury to the underlying myocardium. Future optimization of this energy delivery is required to optimize conditions so that selective electroporation can be utilized in humans the treatment of cardiac disease.
  
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• Cardiac-specific inactivation of effects cardiac conduction abnormalities and cardiomyopathy-associated phenotypes.
  Am J Physiol Heart Circ Physiol

  2020 Feb;():. doi: 10.1152/ajpheart.00647.2019.
  
  Nam Jeong Min, Lim Ji Eun, Ha Tae Woong, Oh Bermseok, Kang Ji-One,
  
  Abstract
  
  A variant in the locus has been correlated with QRS duration in an electrocardiogram genomewide association study, and the deletion of has been implicated as a causal factor of the dilated cardiomyopathy that is linked to 1p36 deletion syndrome. We aimed to determine how a null mutation of affects cardiac function and study the underlying mechanism of the resulting phenotype in an appropriate mouse model. We used cardiac-specific conditional knockout mice to examine cardiac function by electrocardiography. QRS duration and QTc interval increased significantly in cardiac-specific knockout animals compared with wild-type mice. Further, we assessed cardiomyopathy-associated features by trichrome staining, densitometry, and hydroxyproline assay. -null hearts showed greater fibrosis and cardiomyocyte hypertrophy. By quantitative real-time PCR, -null hearts upregulated extracellular matrix-related genes (, ) and a-smooth muscle actin (), a myofibroblast marker. Moreover, TGF-b signaling was activated in -null hearts, as evidenced by increased transcript levels and phosphorylated Smad2. However, the inhibition of TGF-b receptor did not reverse the aberrations in conduction in cardiac-specific knockout mice. To determine the underlying mechanisms, we performed RNA-seq using mouse left ventricular tissue. By functional analysis, -null hearts experienced dysregulated expression of ion channel genes, including , , , and . Mice with -null hearts develop abnormalities in cardiac conduction and cardiomyopathy-associated phenotypes, including fibrosis and cellular hypertrophy. Further, the RNA-seq findings suggest that impairments in ion homeostasis (Ca, K, and Na) may at least partially underlie the abnormal conduction in cardiac-specific knockout mice.
  
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• CYR61/TGF-? axis promotes adventitial fibrosis of Takayasu's arteritis in the IL-17 mediated inflammatory microenvironment.
  Clin Exp Rheumatol

  2020 Feb;():.
  
  Ma Lili, Kong Xiufang, Cui Xiaomeng, Wu Sifan, Wang Yujiao, Dai Xiaomin, Chen Rongyi, Wang Chunsheng, Jiang Lindi,
  
  Abstract
  
  OBJECTIVES:
  Takayasu's arteritis (TAK) is characterised by inflammation and fibrosis in the aortas, but its pathogenesis remains unclear. The aim of the study is to demonstrate the role of cysteine-rich protein 61 (CYR61), a novel proinflammatory factor, in the inflammation and fibrosis of TAK vessels.
  
  METHODS:
  CYR61 expression in the aortic vessel was compared between TA tissues and healthy samples by immunohistochemistry staining. The effect of CYR61 on the proliferation, migration and activation of adventitial fibroblasts (AFs) in the IL-17-mediated inflammatory microenvironment was studied in vitro.
  
  RESULTS:
  Here we found higher expression of CYR61 in the aortic adventitia in TAK patients than in healthy donors by immunohistochemistry staining. In vitro, recombinant human CYR61 (rhCYR61) significantly upregulated the proliferation of primary human aortic adventitial fibroblasts (AFs) and their expression of extracellular matrix (ECM) proteins such as collagen I, collagen III and fibronectin at the mRNA and protein levels, but rhCYR61 partly inhibited the migration of AFs. The integrin ?v?1 was identified as a membrane receptor of CYR61 in AFs, and its downstream Erk1/2 pathway was found activated by detecting its phosphorylation level. Pretreatment with PD98059, an inhibitor of Erk1/2, down-regulated the mRNA and protein expression of ECM proteins in the rhCYR61-stimulated AFs. Furthermore, rhCYR61 up-regulated the expression of TGF-?, and TGF-? siRNA transfection obviously attenuated the profibrotic effect ofrhCYR61. Finally, to clarify the cooperation between CYR61 and classical proinflammatory factors, IL-17 was chosen as a co-stimulator in the culture of AFs. rhIL-17 promoted the mRNA and protein expression of CYR61 in AFs, and the collaboration of rhIL-17 and rhCYR61 dramatically boosted the synthesis of ECM and TGF-?.
  
  CONCLUSIONS:
  Our findings suggest that CYR61 played a profibrotic role through the TGF-? pathway and it enhanced IL-17-mediated inflammation and fibrosis in the mechanism of vascular impairment in TAK.
  
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• Critical role for iron accumulation in the pathogenesis of fibrotic lung disease.
  J Pathol

  2020 Feb;():. doi: 10.1002/path.5401.
  
  Ali Md Khadem, Kim Richard Y, Brown Alexandra C, Donovan Chantal, Vanka Kanth S, Mayall Jemma R, Liu Gang, Pillar Amber L, Jones-Freeman Bernadette, Xenaki Dikaia, Borghuis Theo, Karim Rafia, Pinkerton James W, Aryal Ritambhara, Heidari Moones, Martin Kristy L, Burgess Janette K, Oliver Brian G, Trinder Debbie, Johnstone Daniel M, Milward Elizabeth A, Hansbro Philip M, Horvat Jay C,
  
  Abstract
  
  Increased iron levels and/or dysregulated iron homeostasis occurs in several lung diseases. Here, the effects of iron accumulation on the pathogenesis of pulmonary fibrosis and associated lung function decline was investigated using a combination of murine models of iron overload and bleomycin-induced pulmonary fibrosis, primary human lung fibroblasts treated with iron and histological samples from patients with or without idiopathic pulmonary fibrosis (IPF). Iron levels are significantly increased in iron overloaded transferrin receptor 2 (Tfr2) mutant mice and homeostatic iron regulator (Hfe) gene-deficient mice and this is associated with increases in airways fibrosis and reduced lung function. Furthermore, fibrosis and lung function decline are associated with pulmonary iron accumulation in bleomycin-induced pulmonary fibrosis. We also show that iron accumulation is increased in lung sections from IPF patients and that human lung fibroblasts show greater proliferation, and cytokine and extracellular matrix responses when exposed to increased iron levels. Significantly, we show that intranasal treatment with the iron chelator, deferoxamine (DFO), from the time when pulmonary iron levels accumulate, prevents airway fibrosis and decline in lung function in experimental pulmonary fibrosis. Pulmonary fibrosis is associated with an increase in Tfr1 macrophages that display altered phenotype in disease and DFO treatment modified the abundance of these cells. These experimental and clinical data demonstrate that increased accumulation of pulmonary iron plays a key role in the pathogenesis of pulmonary fibrosis and lung function decline. Furthermore, these data highlight the potential for the therapeutic targeting of increased pulmonary iron in the treatment of fibrotic lung diseases such as IPF. This article is protected by copyright. All rights reserved.
  
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• Idiopathic pulmonary fibrosis: airway volume measurement identifies progressive disease on computed tomography scans.
  ERJ Open Res

  2020 Jan;6(1):. doi: 00290-2019.
  
  McLellan Thomas, George Peter M, Ford Paul, De Backer Jan, Van Holsbeke Cedric, Mignot Benjamin, Screaton Nicholas J, Ruggiero Alessandro, Thillai Muhunthan,
  
  Abstract
  
  http://bit.ly/2M8KVLl.
  
  Copyright ©ERS 2020.
  
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• Osthole down-regulates miR-30a and promotes autophagy to protect rats against myocardial ischemia/reperfusion injury.
  Turk Gogus Kalp Damar Cerrahisi Derg

  2019 Apr;27(2):178-184. doi: 10.5606/tgkdc.dergisi.2019.17294.
  
  Lu Weifeng, He Ying, Yu Tao, Huang Keli, Liu Shengzhong,
  
  Abstract
  
  Background:
  This study aims to investigate the changes in miR-30a expression and myocardial autophagy following osthole treatment in a myocardial ischemia/reperfusion injury model.
  
  Methods:
  Thirty male Wistar rats (weighing 170 to 220 g, aged 8 weeks) were randomly divided into three groups as control (sham) group, ischemia/reperfusion (model) group, and ischemia/ reperfusion + osthole post-treatment (osthole) group. Masson"s trichrome staining was used to detect myocardial collagen changes. Apoptotic cardiomyocytes in the ischemic area were labeled in situ by terminal deoxynucleotidyl transferase-mediated dUTP (2'-deoxyuridine 5'-triphosphate) nick end labeling assay. Levels of autophagy markers light chain 3 beta (LC3b) and Beclin-1 in myocardial tissue were detected by western blotting. Expression of miR-30a was detected by quantitative reverse transcriptionpolymerase chain reaction.
  
  Results:
  Compared with the sham group, ischemia/reperfusion significantly increased collagen contents. Osthole significantly inhibited the ischemia/reperfusion-increased collagen contents. Osthole inhibited the ischemia/reperfusion-increased myocardial fibrosis, myocardial swelling, necrosis, and myocardial atrophy. Osthole also significantly inhibited the ischemia/reperfusionincreased apoptosis of myocardial cells. Moreover, the conversion of LC3b-I to LC3b-II and the Beclin-1 expression were significantly inhibited by ischemia/reperfusion. Osthole treatment significantly increased the conversion of LC3b-I to LC3b-II and Beclin-1 expression in ischemia/reperfusion rats. Finally, the expression of miR-30a was significantly increased in ischemia/reperfusion rats, while Osthole suppressed the expression of miR-30a.
  
  Conclusion:
  Osthole promoted autophagy, thereby alleviating myocardial ischemia/reperfusion injury. Osthole protects the myocardium during autophagy by down-regulating miR-30a expression.
  
  Copyright © 2019, Turkish League Against Rheumatism.
  
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• The Impact of Renal Denervation on the Progression of Heart Failure in a Canine Model Induced by Right Ventricular Rapid Pacing.
  Front Physiol

  2019 ;10():1625. doi: 10.3389/fphys.2019.01625.
  
  Chen Wei-Jie, Liu Hang, Wang Zi-Hao, Liu Chang, Fan Jin-Qi, Wang Zheng-Long, Xu Yan-Ping, Zhang Bo, Gyawali Laxman, Li Qiang, Ling Zhi-Yu, Yin Yue-Hui,
  
  Abstract
  
  Heart failure (HF) has been proposed as a potential indication of renal denervation (RDN). However, the mechanisms enabling RDN to attenuate HF are not well understood, especially the central effects of RDN. The aim of this study was to decipher the mode of operation of RDN in the treatment of HF using a canine model of right ventricular rapid pacing-induced HF. Accordingly, 24 Chinese Kunming dogs were randomly grouped to receive sham procedure (sham-operated group), bilateral RDN (RDN group), rapid pacing to induce HF (HF-control group), and bilateral RDN plus rapid pacing (RDN + HF group). Echocardiography, plasma brain natriuretic peptide (BNP), and norepinephrine (NE) concentrations of randomized dogs were measured at baseline and 4 weeks after interventions, followed by histological and molecular analyses. Twenty dogs completed the research successfully and were enrolled for data analyses. Results showed that the average optical density of renal efferent and afferent nerves were significantly lower in the RDN and RDN + HF groups than in the sham-operated group, with a significant reduction of renal NE concentration. Rapid pacing in the RDN + HF and HF-control groups, compared with the sham-operated group, induced a significant increase in left ventricular end-diastolic volume and decrease in left ventricular ejection fraction and correspondingly resulted in cardiac fibrosis and dysfunction. Cardiac fibrosis evaluated by Masson's trichrome staining and the expression of transforming growth factor-?1 (TGF-?1) were significantly higher in the HF-control group than in the sham-operated group, which were remarkably attenuated by the application of the RDN technique in the RDN + HF group. In terms of central renin-angiotensin system (RAS), the expression of angiotensin II (AngII)/angiotensin-converting enzyme (ACE)/AngII type 1 receptor (AT1R) in the hypothalamus of dogs in the HF-control group, compared with the sham-operated group, was upregulated and that of the angiotensin-(1-7) [Ang-(1-7)]/ACE2 was downregulated. Furthermore, both of them were significantly attenuated by the RDN therapy in the RDN + HF group. In conclusion, the RDN technique could damage renal nerves and suppress the cardiac remodeling procedure in canine with HF while concomitantly attenuating the overactivity of central RAS in the hypothalamus.
  
  Copyright © 2020 Chen, Liu, Wang, Liu, Fan, Wang, Xu, Zhang, Gyawali, Li, Ling and Yin.
  
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• Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA.
  Nat Commun

  2020 Feb;11(1):983. doi: 10.1038/s41467-020-14527-2.
  
  Patel Siddharth, Ashwanikumar N, Robinson Ema, Xia Yan, Mihai Cosmin, Griffith Joseph P, Hou Shangguo, Esposito Adam A, Ketova Tatiana, Welsher Kevin, Joyal John L, Almarsson Örn, Sahay Gaurav,
  
  Abstract
  
  Endosomal sequestration of lipid-based nanoparticles (LNPs) remains a formidable barrier to delivery. Herein, structure-activity analysis of cholesterol analogues reveals that incorporation of C-24 alkyl phytosterols into LNPs (eLNPs) enhances gene transfection and the length of alkyl tail, flexibility of sterol ring and polarity due to -OH group is required to maintain high transfection. Cryo-TEM displays a polyhedral shape for eLNPs compared to spherical LNPs, while x-ray scattering shows little disparity in internal structure. eLNPs exhibit higher cellular uptake and retention, potentially leading to a steady release from the endosomes over time. 3D single-particle tracking shows enhanced intracellular diffusivity of eLNPs relative to LNPs, suggesting eLNP traffic to productive pathways for escape. Our findings show the importance of cholesterol in subcellular transport of LNPs carrying mRNA and emphasize the need for greater insights into surface composition and structural properties of nanoparticles, and their subcellular interactions which enable designs to improve endosomal escape.
  
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• N-Cadherin Overexpression Mobilizes the Protective Effects of Mesenchymal Stromal Cells Against Ischemic Heart Injury Through A ?-Catenin Dependent Manner.
  Circ Res

  2020 Feb;():. doi: 10.1161/CIRCRESAHA.119.315806.
  
  Yan Wenjun, Lin Chen, Guo Yongzhen, Chen Youhu, Du Yunhui, Lau Wayne Bond, Xia Yunlong, Zhang Fuyang, Su Renzhi, Gao Erhe, Wang Yajing, Li Congye, Liu Rui, Ma Xin-Liang, Tao Ling,
  
  Abstract
  
  Mesenchymal stromal cells (MSC)-based therapy is promising against ischemic heart failure (IHF). However, its efficacy is limited due to low cell retention and poor paracrine function. A transmembrane protein capable of enhancing cell-cell adhesion, N-cadherin garnered attention in the field of stem cell biology only recently. The current study investigates whether and how N-cadherin may regulate MSC retention and cardioprotective capability against IHF. Adult mice-derived adipose tissue-derived MSC (ADSC) were transfected with adenovirus harboring N-cadherin (ADSC-Ncad), T-cadherin (ADSC-Tcad), or control adenovirus (ADSC-con). CM-DiI-labeled ADSC were intramyocardially injected into the infarct border zone at 3 sites immediately after myocardial infarction (MI) or myocardial ischemia/reperfusion (MI/R). ADSC retention/survival, cardiomyocyte apoptosis/proliferation, capillary density, cardiac fibrosis, and cardiac function were determined. Discovery-driven/cause-effect analysis was employed to determine the molecular mechanisms. Compared to ADSC-con, N-cadherin overexpression (but not T-cadherin) markedly increased engrafted ADSC survival/retention up to 7 days post-MI. Histological analysis revealed that ADSC-Ncad significantly preserved capillary density and increased cardiomyocyte proliferation, and moderately reduced cardiomyocyte apoptosis 3 days post-MI. More importantly, ADSC-Ncad (but not ADSC-Tcad) significantly increased LVEF and reduced fibrosis in both MI and MI/R mice. In vitro experiments demonstrated that N-cadherin overexpression promoted ADSC-cardiomyocyte adhesion and ADSC migration, enhancing their capability to increase angiogenesis and cardiomyocyte proliferation. MMP-10/13 and/or HGF upregulation is responsible for N-cadherin's effect upon ADSC migration and paracrine angiogenesis. N-cadherin overexpression promotes cardiomyocyte proliferation by HGF release. Mechanistically, N-cadherin overexpression significantly increased N-cadherin/?-catenin complex formation and active ?-catenin levels in the nucleus. ?-catenin knockdown abolished N-cadherin overexpression induced MMP-10, MMP-13, and HGF expression, and blocked the cellular actions and cardioprotective effects of ADSC overexpressing N-cadherin. We demonstrate for the first time that N-cadherin overexpression enhances MSC protective effects against IHF via ?-catenin mediated MMP-10/MMP-13/HGF expression and production, promoting ADSC/cardiomyocyte adhesion and ADSC retention.
  
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• The Crosstalk between Cardiac Lipotoxicity and Mitochondrial Oxidative Stress in the Cardiac Alterations in Diet-Induced Obesity in Rats.
  Cells

  2020 Feb;9(2):. doi: E451.
  
  Jiménez-González Sara, Marín-Royo Gema, Jurado-López Raquel, Bartolomé María Visitación, Romero-Miranda Ana, Luaces María, Islas Fabián, Nieto María Luisa, Martínez-Martínez Ernesto, Cachofeiro Victoria,
  
  Abstract
  
  The impact of the mitochondria-targeted antioxidant MitoQ was evaluated in the cardiac alterations associated with obesity. Male Wistar rats were fed either a high fat diet (HFD, 35% fat) or a standard diet (CT, 3.5% fat) for 7 weeks and treated with MitoQ (200 µM). The effect of MitoQ (5 nM) in rat cardiac myoblasts treated for 24 h with palmitic acid (PA, 200 µM) was evaluated. MitoQ reduced cardiac oxidative stress and prevented the development of cardiac fibrosis, hypertrophy, myocardial -FDG uptake reduction, and mitochondrial lipid remodeling in HFD rats. It also ameliorated cardiac mitochondrial protein level changes observed in HFD: reductions in fumarate hydratase, complex I and II, as well as increases in mitofusin 1 (MFN1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and cyclophilin F (cycloF). In vitro, MitoQ prevented oxidative stress and ameliorated alterations in mitochondrial proteins observed in palmitic acid (PA)-stimulated cardiac myoblasts: increases in carnitine palmitoyltransferase 1A, cycloF, and cytochrome C. PA induced phosphorylation of extracellular signal-regulated kinases and nuclear factor-?B p65. Therefore, the data show the beneficial effects of MitoQ in the cardiac damage induced by obesity and suggests a crosstalk between lipotoxicity and mitochondrial oxidative stress in this damage.
  
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• Pulmonary artery enlargement is associated with pulmonary hypertension and decreased survival in severe cystic fibrosis: A cohort study.
  PLoS One

  2020 ;15(2):e0229173. doi: 10.1371/journal.pone.0229173.
  
  Zouk Aline N, Gulati Swati, Xing Dongqi, Wille Keith M, Rowe Steven M, Wells J Michael,
  
  Abstract
  
  BACKGROUND:
  Pulmonary artery (PA) enlargement, defined as pulmonary artery to ascending aorta diameter ratio (PA:A)>1 on computed tomography (CT), is a marker of pulmonary vascular disease in chronic lung diseases. PA enlargement is prevalent in cystic fibrosis (CF), but its relationship to hemodynamics and prognostic utility in severe CF are unknown. We hypothesized that the PA:A would have utility in identifying pulmonary hypertension (PH) in severe CF and that PA enlargement would be associated with reduced transplant-free survival.
  
  METHODS:
  We conducted a retrospective study of adults with CF undergoing lung transplant evaluation at a single center between 2000 and 2015. CT, right heart catheterization (RHC), and clinical data were collected. The PA:A was measured from a single CT slice. We measured associations between PA:A and invasive hemodynamic parameters including PH defined as a mPAP ?25mmHg using adjusted linear and logistic regression models. Kaplan-Meier and adjusted Cox regression models were used to measure associations between PA:A>1, RHC-defined PH, and transplant-free survival in severe CF.
  
  RESULTS:
  We analyzed 78 adults with CF that had CT scans available for review, including 44 that also had RHC. RHC-defined PH defined as a mPAP ?25mmHg was present in 36% of patients with CF undergoing transplant evaluation. The PA:A correlated with mPAP (r = 0.73; 95% CI 3.87-7.80; p<0.001) and PVR (r = 0.42, p = 0.005) and the PA:A>1 was an independent predictor of PH (aOR 4.50; 95% CI 1.05-19.2; p = 0.042). PA:A>1 was independently associated with increased hazards for death or transplant (aHR 2.69; 95% CI 1.41-5.14; P = 0.003). The presence of mPAP ?25mmHg was independently associated with decreased survival in this cohort.
  
  CONCLUSIONS:
  PA enlargement is associated with pulmonary hemodynamics and PH in severe CF. PA enlargement is an independent prognostic indicator of PH and decreased survival in this population.
  
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• Angiocrine FSTL1 (Follistatin-Like Protein 1) Insufficiency Leads to Atrial and Venous Wall Fibrosis via SMAD3 Activation.
  Arterioscler Thromb Vasc Biol

  2020 Feb;():ATVBAHA119313901. doi: 10.1161/ATVBAHA.119.313901.
  
  Jiang Haijuan, Zhang Luqing, Liu Xuelian, Sun Wei, Kato Katsuhiro, Chen Chuankai, Li Xiao, Li Taotao, Sun Zhiliang, Han Wencan, Zhang Fujing, Xiao Qi, Yang Zhongzhou, Hu Junhao, Qin Zhihai, Adams Ralf H, Gao Xiang, He Yulong,
  
  Abstract
  
  OBJECTIVE:
  Angiocrine factors, mediating the endothelial-mural cell interaction in vascular wall construction as well as maintenance, are incompletely characterized. This study aims to investigate the role of endothelial cell-derived FSTL1 (follistatin-like protein 1) in vascular homeostasis. Approach and Results: Using conditional knockout mouse models, we show that loss of FSTL1 in endothelial cells () led to an increase of pulmonary vascular resistance, resulting in the heart regurgitation especially with tricuspid valves. However, this abnormality was not detected in mutant mice with deletion in smooth muscle cells or hematopoietic cells. We further showed that there was excessive ?SMA (?-smooth muscle actin) associated with atrial endocardia, heart valves, veins, and microvessels after the endothelial FSTL1 deletion. There was also an increase in collagen deposition, as demonstrated in livers of mutants. The SMAD3 phosphorylation was significantly enhanced, and pSMAD3 staining was colocalized with ?SMA in vein walls, suggesting the activation of TGF? (transforming growth factor ?) signaling in vascular mural cells of mice. Consistently, treatment with a TGF? pathway inhibitor reduced the abnormal association of ?SMA with the atria and blood vessels in mutant mice.
  
  CONCLUSIONS:
  The findings imply that endothelial FSTL1 is critical for the homeostasis of vascular walls, and its insufficiency may favor cardiovascular fibrosis leading to heart failure.
  
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• Contrast-free high-resolution 3D magnetization transfer imaging for simultaneous myocardial scar and cardiac vein visualization.
  MAGMA

  2020 Feb;():. doi: 10.1007/s10334-020-00833-9.
  
  López Karina, Neji Radhouene, Mukherjee Rahul K, Whitaker John, Phinikaridou Alkystis, Razavi Reza, Prieto Claudia, Roujol Sébastien, Botnar René,
  
  Abstract
  
  OBJECTIVE:
  To develop a three-dimensional (3D) high-resolution free-breathing magnetization transfer ratio (MTR) sequence for contrast-free assessment of myocardial infarct and coronary vein anatomy.
  
  MATERIALS AND METHODS:
  Two datasets with and without off-resonance magnetization transfer preparation were sequentially acquired to compute MTR. 2D image navigators enabled beat-to-beat translational and bin-to-bin non-rigid motion correction. Two different imaging sequences were explored. MTR scar localization was compared against 3D late gadolinium enhancement (LGE) in a porcine model of myocardial infarction. MTR variability across the left ventricle and vessel sharpness in the coronary veins were evaluated in healthy human subjects.
  
  RESULTS:
  A decrease in MTR was observed in areas with LGE in all pigs (non-infarct: 25.1?±?1.7% vs infarct: 16.8?±?1.9%). The average infarct volume overlap on MTR and LGE was 62.5?±?19.2%. In humans, mean MTR in myocardium was between 37 and 40%. Spatial variability was between 15 and 20% of the mean value. 3D whole heart MT-prepared datasets enabled coronary vein visualization with up to 8% improved vessel sharpness for non-rigid compared to translational motion correction.
  
  DISCUSSION:
  MTR and LGE showed agreement in infarct detection and localization in a swine model. Free-breathing 3D MTR maps are feasible in humans but high spatial variability was observed. Further clinical studies are warranted.
  
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• Current management of non-alcoholic steatohepatitis.
  Liver Int

  2020 Feb;40 Suppl 1():89-95. doi: 10.1111/liv.14355.
  
  Muthiah Mark D, Sanyal Arun J,
  
  Abstract
  
  Non-alcoholic steatohepatitis (NASH) is the most common cause of liver disease in Western populations, and its prevalence is increasing rapidly. It is part of a multisystem disease affecting other organs such as the kidneys, heart and blood vessels, and is closely associated with the components of the metabolic syndrome. Physicians managing patients with NASH should not only focus on the management of NASH, but also on associated comorbidities in individual patients. The approaches to treatment of NASH include either limiting energy surplus alone, or in combination with targeting of downstream pathways of inflammation and fibrosis. In this mini-review, we discuss the currently available treatment options for NASH, as well as those in late-stage clinical trials. We discuss the challenges of managing these patients with a limited number of approved therapies, as well as managing advanced-stage patients with NASH and cirrhosis. We also discuss the specific management of comorbidities in NASH patients, in particular diabetes, hypertension, dyslipidaemia and cardiovascular diseases. Finally, we present the screening protocols for both hepatocellular carcinoma and extrahepatic malignancies in these patients.
  
  © 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
  
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