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Pubblicazioni recenti - cardiac fibrosis
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The homozygous variant c.245G>A/p.G82D in PNPLA2 is associated with arrhythmogenic cardiomyopathy phenotypic manifestations.
Clin Genet2019 Sep;():. doi: 10.1111/cge.13642.
Rao Man, Guo Guang-Ran, Li Meng-Meng, Chen Shi, Chen Kai, Chen Xiao, Song Jiang-Ping, Hu Sheng-Shou,
Abstract
Arrhythmogenic cardiomyopathy (ACM) is a familial cardiomyopathy featured by fibro-fatty replacement of cardiomyocytes. Responsible genetic factors are not discernible in approximately one third of ACM probands. To investigate this further, we performed whole genome sequencing (WGS) in 14 mutation-negative ACM probands who underwent cardiac transplantation, and we identified one ACM proband with a rare homozygous missense variant in PNPLA2 (c.245G>A, p.G82D), a rate-limiting enzyme that hydrolyzes triglycerides into fatty-acids and diacylglycerol. Bioinformatic analysis suggested that this missense variant may lead to loss-of-function and therefore impair lipid catabolism. Genetic screening in this proband's family also inferred that the homozygous variant co-segregated with disease. To validate the pathogenicity of this variant and confirm its association with ACM, we established a knock-in mouse model carrying the orthologous human homozygous PNPLA2 variant. Interestingly, mice with the homozygous variant presented with arrhythmias and significant cardiac dysfunction at 12-weeks, whereas heterozygous mice were not affected. Moreover, those homozygous mice suffered sudden death and/or heart failure by age of 14-weeks. Pathological examination showed that extensive lipogenesis in cardiomyocytes and cardiac fibrosis were prominent in the myocardium. Herein, our data demonstrated that the homozygous missense variant PNPLA2 (c.245G>A, p.G82D) associated with a recessive form of ACM. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
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Increased expression of Sonic hedgehog restores diabetic endothelial progenitor cells and improves cardiac repair after acute myocardial infarction in diabetic mice.
Int J Mol Med2019 Jul;():. doi: 10.3892/ijmm.2019.4277.
Xiao Qing, Zhao Xiao-Ya, Jiang Ru-Chao, Chen Xiu-Hui, Zhu Xiang, Chen Kai-Feng, Chen Sheng-Ying, Zhang Xiao-Ling, Qin Yuan, Liu Ying-Hua, Luo Jian-Dong,
Abstract
Damaged endothelial progenitor cells (EPCs) are associated with poor prognosis in diabetic myocardial infarction (DMI). Our previous studies revealed that an impaired Sonic hedgehog (Shh) pathway contributes to insufficient function in diabetic EPCs; however, the roles of the Shh pathway in diabetic EPC apoptosis under basal and hypoxic/ischemic conditions remain unknown. Therefore, the present study investigated whether Shh revitalized diabetic EPCs and consequently improved the deteriorative status of DMI. For this purpose, streptozotocin injection was used in male C57/BL6 mice to induce type?1 diabetes, and diabetic EPCs were isolated from the bone marrow. Apoptosis, cell function, and protein expression were investigated in EPCs in vitro. Mouse hearts were injected with adenovirus Shh?modified diabetic EPCs (DM?EPCShh) or control DM?EPCNull immediately after coronary artery ligation in vivo. Cardiac function, capillary numbers, fibrosis, and cell apoptosis were then detected. First, the in vitro results demonstrated that the apoptosis of diabetic EPCs was reduced following treatment with Shh protein for 24 h, under normal or hypoxic conditions. BMI1 proto?oncogene (Bmi1), an antiapoptotic protein found in several cells, was reduced in diabetic EPCs under normal or hypoxic conditions, but was upregulated after Shh protein stimulation. When Bmi1?siRNA was administered, the antiapoptotic effect of Shh protein was significantly reversed. In addition, p53, a Bmi1?targeted gene, was demonstrated to mediate the antiapoptotic effect of the Shh/Bmi1 pathway in diabetic EPCs. The Shh/Bmi1/p53 axis also enhanced the diabetic EPC function. In vivo, Shh?modified diabetic EPCs exhibited increased EPC retention and decreased apoptosis at 3 days post?DMI. At 14 days post?DMI, these cells presented enhanced capillary density, reduced myocardial fibrosis and improved cardiac function. In conclusion, the present results demonstrated that the Shh pathway restored diabetic EPCs through the Shh/Bmi1/p53 axis, suppressed myocardial apoptosis and improved myocardial angiogenesis, thus reducing cardiac fibrosis and finally restoring myocardial repair and cardiac function in DMI. Thus, the Shh pathway may serve as a potential target for autologous cell therapy in diabetic myocardial ischemia.
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Evaluation of the effects of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR-Preserved Trial.
Eur J Heart Fail2019 Sep;():. doi: 10.1002/ejhf.1596.
Anker Stefan D, Butler Javed, Filippatos Gerasimos S, Jamal Waheed, Salsali Afshin, Schnee Janet, Kimura Karen, Zeller Cordula, George Jyothis, Brueckmann Martina, Zannad Faiez, Packer Milton, ,
Abstract
BACKGROUND:
The principal biological processes that characterize heart failure with a preserved ejection fraction (HFpEF) are systemic inflammation, epicardial adipose tissue accumulation, coronary microcirculatory rarefaction, myocardial fibrosis and vascular stiffness; the resulting impairment of left ventricular and aortic distensibility (especially when accompanied by impaired glomerular function and sodium retention) causes increases in cardiac filling pressures and exertional dyspnoea despite the relative preservation of left ventricular ejection fraction. Independently of their actions on blood glucose, sodium-glucose co-transporter 2 (SGLT2) inhibitors exert a broad range of biological effects (including actions to inhibit cardiac inflammation and fibrosis, antagonize sodium retention and improve glomerular function) that can ameliorate the pathophysiological derangements in HFpEF. Such SGLT2 inhibitors exert favourable effects in experimental models of HFpEF and have been found in large-scale trials to reduce the risk for serious heart failure events in patients with type?2 diabetes, many of whom were retrospectively identified as having HFpEF.
STUDY DESIGN:
The EMPEROR-Preserved Trial is enrolling ?5750 patients with HFpEF (ejection fraction >40%), with and without type 2 diabetes, who are randomized to receive placebo or empagliflozin 10 mg/day, which is added to all appropriate treatments for HFpEF and co-morbidities.
STUDY AIMS:
The primary endpoint is the time-to-first-event analysis of the combined risk for cardiovascular death or hospitalization for heart failure. The trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all-cause mortality and recurrent hospitalization events, and will assess a wide range of biomarkers that reflect important pathophysiological mechanisms that may drive the evolution of HFpEF. The EMPEROR-Preserved Trial is well positioned to determine if empagliflozin can have a meaningful impact on the course of HFpEF, a disorder for which there are currently few therapeutic options.
© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.
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Dysregulation of the Renin-Angiotensin System and Cardiometabolic Status in Mice Fed a Long-Term High-Fat Diet.
Med Sci Monit2019 Sep;25():6605-6614. doi: 10.12659/MSM.914877.
Jin Nana, Wang Yu, Liu Lin, Xue Feng, Jiang Tingbo, Xu Mingzhu,
Abstract
BACKGROUND This study aimed to investigate the renin-angiotensin system (RAS) and cardiometabolic status in mice fed a long-term high-fat diet (HFD). MATERIAL AND METHODS C57BL/6J mice were randomly assigned to the control group on a normal diet (ND) (n=15) and the HFD group (n=15). Serum biomarkers were measured, including total cholesterol (TC), triglyceride (TG), insulin, glycated hemoglobin (HbA1c), brain natriuretic peptide (BNP), renin, angiotensin-converting enzyme (ACE), angiotensin II (Ang-II), Ang-II type 1 receptor (AT?R), and aldosterone. Cardiac histology was measured by the cross-sectional area (CSA) of cardiomyocytes and collagen deposition. Levels of myocardial intercalated disc (ICD) proteins and mRNA were analyzed by Western blot and real-time quantitative polymerase chain reaction (RT-qPCR), respectively. The localization of ICD proteins was evaluated by immunohistochemistry (IHC). RESULTS Compared with ND, HFD resulted in increased blood glucose, body weight, TC, TG, HbA1c, insulin, and BNP and levels of serum ACE, Ang-II, aldosterone, AT?R, cardiomyocyte CSA, and interstitial collagen in the myocardium compared. Also, HFD significantly down-regulated connexin-43, and upregulated ß-catenin, N-cadherin, and plakoglobin in the hearts of HFD mice compared with ND mice. However, the deposition of ICD proteins was not changed in the hearts of HFD mice compared with ND mice. CONCLUSIONS Long-term HFD in mice resulted in left ventricular hypertrophy, interstitial fibrosis, dysregulation of RAS, and abnormal expression of ICD proteins compared with ND mice, but did not affect the distribution of cardiomyocyte ICD proteins. Long-term HFD resulted in cardiac remodeling and altered expression of ICD proteins through RAS activation.
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Prior Sternotomy in Transvenous Lead Extraction: Risk Analysis Tempered by Clinical Experience.
Circ Arrhythm Electrophysiol2019 Sep;12(9):e007762. doi: 10.1161/CIRCEP.119.007762.
Eskander Michael A, Pretorius Victor, Birgersdotter-Green Ulrika,
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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 Release2019 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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Estimated Ventricular Size, Asthma Severity and Exacerbations: The SARP III Cohort.
Chest2019 Sep;():. doi: S0012-3692(19)33744-4.
Ash Samuel Y, Vegas Sanchez-Ferrero Gonzalo, Schiebler Mark L, Rahaghi Farbod N, Rai Ashish, Come Carolyn E, Ross James C, Colon Alysha G, Cardet Juan Carlos, Bleecker Eugene R, Castro Mario, Fahy John V, Fain Sean B, Gaston Benjamin M, Hoffman Eric A, Jarjour Nizar N, Lempel Jason K, Mauger David T, Tattersall Matthew C, Wenzel Sally E, Levy Bruce D, Washko George R, Israel Elliot, San Jose Estepar Raul, ,
Abstract
BACKGROUND:
Relative enlargement of the pulmonary artery (PA) on chest computed tomography (CT) is associated with respiratory exacerbations in patients with chronic obstructive pulmonary disease or cystic fibrosis. We sought to determine if similar findings were present in patients with asthma and if they were explained by differences in ventricular size.
METHODS:
We measured the PA and aorta diameters in 233 individuals from the Severe Asthma Research Program III cohort. We also estimated right, left and total epicardial cardiac ventricular volume indices (eERVVI, eELVVI and eETVVI respectively). Associations between the cardiac and PA measures (PA to aorta ratio (PA/A), eERVVI to eELVVI ratio (eRV/eLV), eERVVI, eELVVI, eETVVI) and clinical measures of asthma severity were assessed using Pearson correlation, and associations with asthma severity and exacerbation rate were evaluated using multivariable linear and zero-inflated negative binomial regression.
RESULTS:
Asthma severity was associated with smaller ventricular volumes. For example, those with severe asthma had 36.1 mL/m smaller eETVVI than healthy controls (p=0.003) and 14.1 mL/m smaller eETVVI than those with mild/moderate disease (p=0.011). Smaller ventricular volumes were also associated with a higher rate of asthma exacerbations, both retrospectively and prospectively. For example, those with an eETVVI less than the median had a 57% higher rate of exacerbations during follow up than those with eETVVI greater than the median (p=0.020). Neither PA/A nor eRV/eLV were associated with asthma severity or exacerbations.
CONCLUSIONS:
In asthmatics, smaller cardiac ventricular size may be associated with more severe disease and a higher rate of asthma exacerbations.
Copyright © 2019. Published by Elsevier Inc.
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The axis of local cardiac endogenous Klotho-TGF-?1-Wnt signaling mediates cardiac fibrosis in human.
J Mol Cell Cardiol2019 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 Fail2019 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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Mycophenolate mofetil as an alternative treatment in sarcoidosis.
Pulm Pharmacol Ther2019 Sep;58():101840. doi: S1094-5539(19)30188-9.
Papiris Spyros, Stagaki Eleni, Papadaki Georgia, Kolilekas Lykourgos, Korbila Ioanna, Apollonatou Vassiliki, Kallieri Maria, Gialafos Helias, Chatziioannou Sofia, Papaioannou Adriana I, Manali Effrosyni D,
Abstract
INTRODUCTION:
In sarcoidosis although no better drug therapy than corticosteroids (CS) has emerged, alternative immunosuppressive agents are used when indicated. Mycophenolate mofetil (MMF) presents rapid action, a considerable safety profile and absence of lung toxicity. Few data exist so far on its use in patients with sarcoidosis. This is a retrospective study on the effectiveness and safety of MMF in patients with sarcoidosis.
MATERIALS AND METHODS:
All patients with biopsy proven sarcoidosis treated for at least 1 year with MMF from 2008 to 2017 in our department are evaluated.
RESULTS:
Eight patients with both pulmonary and extrapulmonary disease are included in the analysis. During follow-up, symptoms and chest radiological findings improved in all. A statistically significant improvement of FEV and FVC is reported (p?=?0.010 and p?=?0.021 respectively). Cardiac and renal disease resolved during treatment while dermal disease significantly improved. MMF permitted CS dose reduction from 15.0 (10.0, 35.0) to 2.5 (0.0, 5.0) mg prednisolone (or equivalent), p?=?0.016. All patients but one, tolerated well MMF.
CONCLUSION:
MMF as an alternative drug in systemic sarcoidosis, proved safe and effective, permitting the reduction of the dose of oral CS and leading to clinical, functional and radiological improvement.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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Retinoic acid attenuates cardiac injury induced by hyperglycemia in pre- and post-delivery mice.
Can J Physiol Pharmacol2019 Sep;():. doi: 10.1139/cjpp-2019-0009.
Liu Yun, Zhao Jinsong, Lu Meili, Wang Hongxing, Tang Futian,
Abstract
The aim of the present study is to explore the effect of retinoic acid (RA) on cardiac injury induced by gestational diabetes mellitus (GDM). GDM mice were given 3 mg/kg RA once daily until the 19th day of pregnancy or the 7th day of postpartum. Compared to normal control and normal pregnant control mice, GDM mice before and after delivery showed significantly cardiac injury. RA treatment attenuated cardiac injury as evidenced by decreased heart weight and left ventricular mass, mRNA expressions of ANP and BNP and cardiac fibrosis compared with that in GDM mice. The protective effect of RA on GDM cardiomyopathy was related with the decreased MDA content and ROS generation, the increased GSH-Px and SOD content, as well as the reduced TNF-? and IL-1? content and inhibition of NF-?B signaling. In addition, RA treatment delayed the continuous rise of blood glucose before delivery, and decreased the higher level of glucose after delivery. In conclusion, RA treatment could increase the activity of the antioxidant enzyme, suppress the oxidative stress, inflammation response and activation of NF-?B signaling, thereby improving blood glucose level and cardiac injury of GDM mice before and after delivery.
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Gene expression profiling of the bone trabecula in patients with osteonecrosis of the femoral head by RNA sequencing.
J Biochem2019 Sep;():. doi: mvz060.
Bai Haobo, Chen Tingmei, Lu Qian, Zhu Weiwen, Zhang Jian,
Abstract
Early diagnosis and treatment of osteonecrosis of the femoral head (ONFH) is challenging. Bone trabecula play a vital role in the severity and progression of ONFH. In the present study, the investigators used gene expression profiling of bone trabecula to investigate gene alterations in ONFH patients. Osteonecrotic bone trabecula (ONBT) such as necrosis, fibrosis, and lacuna were confirmed by histological examination in the patients. The adjacent ''normal'' bone trabecula (ANBT) did not show any pathological changes. Gene sequencing data revealed that although ANBT showed no significant histological changes, alteration of mRNA profiling in ANBT was observed, similarly to that in ONBT. Our results indicated that the alteration of mRNA profiling in ANBT may cause normal bone tissue to develop into necrotic bone. RNA-seq data indicated that 2297 differentially abundant mRNAs were found in the ONBT group (1032 upregulated and 1265 downregulated) and 1523 differentially abundant mRNAs in the ANBT group (744 upregulated and 799 downregulated) compared with the healthy control group. GO enrichment analysis suggested that fatty acid metabolism and degradation were the main zones enriched with differentially expressed genes (DEG). KEGG pathway enrichment analysis indicated that PPAR? pathway was the most significantly regulated pathway. Lipocalin-2 (LCN2), an osteoblast-enriched secreted protein, was significantly decreased in ONBT suggesting that downregulation of LCN2 might affect lipid metabolism and lead to hyperlipidemia, and thus promote pathogenesis of ONFH.
© The Author(s) 2019. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.
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Extracellular DNA NET-Works With Dire Consequences for Health.
Circ Res2019 Aug;125(4):470-488. doi: 10.1161/CIRCRESAHA.119.314581.
Sorvillo Nicoletta, Cherpokova Deya, Martinod Kimberly, Wagner Denisa D,
Abstract
Neutrophils play a central role in innate immune defense. Advances in neutrophil biology have brought to light the capacity of neutrophils to release their decondensed chromatin and form large extracellular DNA networks called neutrophil extracellular traps (NETs). NETs are produced in response to many infectious and noninfectious stimuli and, together with fibrin, block the invasion of pathogens. However, their formation in inflamed blood vessels produces a scaffold that supports thrombosis, generates neo-antigens favoring autoimmunity, and aggravates damage in ischemia/reperfusion injury. NET formation can also be induced by cancer and promotes tumor progression. Formation of NETs within organs can be immediately detrimental, such as in lung alveoli, where they affect respiration, or they can be harmful over longer periods of time. For example, NETs initiate excessive deposition of collagen, resulting in fibrosis, thus likely contributing to heart failure. Here, we summarize the latest knowledge on NET generation and discuss how excessive NET formation mediates propagation of thrombosis and inflammation and, thereby, contributes to various diseases. There are many ways in which NET formation could be averted or NETs neutralized to prevent their detrimental consequences, and we will provide an overview of these possibilities.
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Impaired function of aorta and perivascular adipose tissue in IL-18-deficient mice.
Am J Physiol Heart Circ Physiol2019 Sep;():. doi: 10.1152/ajpheart.00813.2018.
Li Wen, Jin Denan, Takai Shinji, Hayakawa Tetsu, Ogata Jun, Yamanishi Kyosuke, Yamanishi Hiromichi, Okamura Haruki,
Abstract
Interleukin-18 (IL-18) is ubiquitously produced by both hematopoietic and non-hematopoietic cells, but the central biological role of IL-18 in non-hematopoietic cells has not been sufficiently elucidated. In the present study, we examined the thoracic aorta, including perivascular adipose tissue (PVAT) of the IL-18 knockout (KO) mice in terms of functional and histological aspects.?IL-18KO mice exhibited significantly higher blood pressure compared with wild-type (WT) mice. Echocardiographic examination showed a thickened vascular wall and narrowed vascular diameter of the abdominal aorta. Examination by the Magnus test demonstrated dysfunction of endothelial cells (EC) in the IL-18KO thoracic aorta and impairment of the anti-contractile function of IL-18KO PVAT. Histological examination showed no inflammatory lesions in the aorta, but indicated progressive fibrosis in the vessel, conversion of PVAT from brown adipose tissue-like features to white adipose tissue-like features, and heterogeneous localizations of claudin 5 in the PVAT of IL-18KO mice. Electron microscopic observation revealed several deformed mitochondria in the EC and PVAT, and many vacuoles in the EC of the IL-18KO aorta. ATP productivity and activity of complex IV were decreased in the mitochondria of IL-18KO aorta, and production of reactive oxygen species was augmented. Western blot analysis revealed that a decreased expression of MnSOD, while that of UCP1 and LAMP 1/2 was increased in mitochondria of IL-18KO PVAT. Moreover, cathepsin D activity was decreased in IL-18KO PVAT. Thus, the IL-18KO thoracic aorta had defects in physiological functions related to histological?alterations, which might have been associated with mitochondrial dysfunction in IL-18KO mice.
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Native T1 time and extracellular volume fraction in differentiation of normal myocardium from non-ischemic dilated and hypertrophic cardiomyopathy myocardium: A systematic review and meta-analysis.
Int J Cardiol Heart Vasc2019 Dec;25():100422. doi: 10.1016/j.ijcha.2019.100422.
Minegishi Shintaro, Kato Shingo, Takase-Minegishi Kaoru, Horita Nobuyuki, Azushima Kengo, Wakui Hiromichi, Ishigami Tomoaki, Kosuge Masami, Kimura Kazuo, Tamura Kouichi,
Abstract
Background:
Both native T1 time and extracellular volume (ECV) fraction have been shown to be important measures for the detection of myocardial fibrosis. However, ECV determination requires the administration of an intravenous contrast agent, whereas native T1 mapping can be performed without a contrast agent.
Methods:
Here, we conducted a meta-analysis of myocardial native T1 data obtained for non-ischemic cardiomyopathy (NIC) patients and controls. A literature review included studies that applied T1 mapping using modified Look-Locker inversion recovery to measure myocardial fibrosis, and the results were validated by comparing datasets for dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM) patients and healthy controls (HCs).
Results:
We identified 16 eligible studies. Pooled mean differences (MDs) and 95% confidence intervals (CIs) were estimated as follows. Native T1 at 1.5-T, DCM vs. HC: MD?=?45.26 (95% CI: 30.92-59.59); HCM vs. HC: MD?=?47.09 (95% CI: 32.42-61.76). Native T1 at 3.0-T, DCM vs. HC: MD?=?82.52 (95% CI: 47.60-117.44); HCM vs. HC: MD?=?115.87 (95% CI: 50.71-181.04). ECV at 1.5-T, DCM vs. HC: MD?=?4.26 (95% CI: 3.06-5.46); HCM vs. HC: MD?=?1.49 (95% CI: -1.45-4.43). ECV at 3.0-T, DCM vs. HC: MD?=?8.40 (95% CI: 2.94-13.86); HCM vs. HC: MD?=?8.02 (95% CI: 5.45-1-0.59).
Conclusion:
In conclusion, native T1 values were significantly different between NIC patients and controls. Native T1 mapping may be a useful noninvasive method to detect diffuse myocardial fibrosis in NIC patients.
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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 Sin2019 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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Pulmonary fibrosis linked to variants in the gene, encoding the telomere protein TPP1.
Eur Respir J2019 Sep;():. doi: 1900809.
Hoffman Thijs W, van der Vis Joanne J, van der Smagt Jasper J, Massink Maarten P G, Grutters Jan C, van Moorsel Coline H M,
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Catalpol in Diabetes and its Complications: A Review of Pharmacology, Pharmacokinetics, and Safety.
Molecules2019 Sep;24(18):. doi: E3302.
Bai Ying, Zhu Ruyuan, Tian Yimiao, Li Rui, Chen Beibei, Zhang Hao, Xia Bingke, Zhao Dandan, Mo Fangfang, Zhang Dongwei, Gao Sihua,
Abstract
This review aimed to provide a general view of catalpol in protection against diabetes and diabetic complications, as well as its pharmacokinetics and safety concerns. The following databases were consulted with the retrieval of more than 100 publications through June 2019: PubMed, Chinese National Knowledge Infrastructure, WanFang Data, and web of science. Catalpol exerts an anti-diabetic effect in different animal models with an oral dosage ranging from 2.5 to 200 mg/kg in rats and 10 to 200 mg/kg in mice. Besides, catalpol may prevent the development of diabetic complications in kidney, heart, central nervous system, and bone. The underlying mechanism may be associated with an inhibition of inflammation, oxidative stress, and apoptosis through modulation of various cellular signaling, such as AMPK/PI3K/Akt, PPAR/ACC, JNK/NF-?B, and AGE/RAGE/NOX4 signaling pathways, as well as PKC? and Cav-1 expression. The pharmacokinetic profile reveals that catalpol could pass the blood-brain barrier and has a potential to be orally administrated. Taken together, catalpol is a well-tolerated natural compound with promising pharmacological actions in protection against diabetes and diabetic complications via multi-targets, offering a novel scaffold for the development of anti-diabetic drug candidate. Further prospective and well-designed clinical trials will shed light on the potential of clinical usage of catalpol.
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LTBP2 knockdown by siRNA reverses myocardial oxidative stress injury, fibrosis, and remodeling during dilated cardiomyopathy.
Acta Physiol (Oxf)2019 Sep;():. doi: 10.1111/apha.13377.
Pang Xue-Feng, Lin Xue, Du Jian-Jun, Zeng Ding-Yin,
Abstract
AIM:
Dilated cardiomyopathy (DCM) is is characterised by left ventricular dilation and associated with systolic dysfunction. Recent evidence has reported the high expression of latent transforming growth factor beta-binding protein 2 (LTBP2) in heart diseases, which may play a role in regulating multiple biological functions of myocardial cells. Thus, this study set out to investigate the molecular mechanism and effects of LTBP2 in myocardial oxidative stress injury, fibrosis and remodeling in a rat model of DCM, with the involvement of NF-?B signaling pathway.
METHODS:
The rat model of DCM was treated with si-LTBP2 and/or activator of NF-?B signaling pathway to examine the hemodynamic indexes, cardiac functions, oxidative stress injury, fibrosis and remodeling. Moreover, in vitro experiments were conducted to verify the regulatory role of LTBP2 and NF-?B signaling pathway in DCM.
RESULTS:
LTBP2 was upregulated in DCM rats. After LTBP2 was knocked down, hemodynamic indexes, HW/BW ratio, collagen volume fraction (CVF) level, positive expression of LTBP2, levels of reactive oxygen species (ROS), malondialdehyde (MDA), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-?), tumor necrosis factor-beta 1 (TGF-?1) and brain natriuretic peptide (BNP) were all decreased. Meanwhile, levels of LTBP2, Col-I, Col-III, p65 and p52 were also reduced, while HW, BW and levels of SOD and TAOC were increased. In contrast, activation of NF-?B signaling pathway reversed effects of LTBP2 gene silencing. These findings were confirmed by in vivo experiments.
CONCLUSIONS:
LTBP2 silencing can attenuate myocardial oxidative stress injury, myocardial fibrosis and myocardial remodeling in DCM rats by down-regulating NF-?B signaling pathway.
© 2019 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.
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Anti-fibrotic effects of curcumin and some of its analogues in the heart.
Heart Fail Rev2019 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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