SOSTIENICI
Pubblicazioni recenti - cardiac fibroblast
-
KLB dysregulation mediates disrupted muscle development in intrauterine growth restriction.
J Physiol2022 Jan;():. doi: 10.1113/JP281647.
Cortes-Araya Yennifer, Stenhouse Claire, Salavati Mazdak, Dan-Jumbo Susan O, Ho William, Ashworth Cheryl J, Clark Emily, Esteves Cristina L, Donadeu F Xavier,
Abstract
KEY POINTS:
IUGR is associated with large-scale transcriptional changes in developmental, tissue injury and metabolic gene pathways in fetal skeletal muscle. Levels of the FGF21 co-receptor, KLB, are increased in IUGR fetal muscle, and FGF21 concentrations are increased in IUGR fetal plasma KLB mediates a reduction in muscle development through inhibition of mTOR signaling. These effects of KLB on muscle cells are conserved in pig and human, suggesting a vital role of this protein in the regulation of muscle development and function in mammals.
ABSTRACT:
Intrauterine growth restriction (IUGR) is a leading cause of neonatal morbidity and mortality in humans and domestic animals. Developmental adaptations of skeletal muscle in IUGR lead to increased risk of premature muscle loss and metabolic disease in later life. Here, we identified ?-Klotho (KLB), a Fibroblast Growth Factor 21 (FGF21) co-receptor, as a novel regulator of muscle development in IUGR. Using the pig as a naturally-occurring disease model, we performed transcriptome-wide profiling of fetal muscle (day 90 of pregnancy) from IUGR and normal-weight (NW) littermates. We found that, alongside large-scale transcriptional changes comprising multiple developmental, tissue injury and metabolic gene pathways, KLB was increased in IUGR muscle. Moreover, FGF21 concentrations were increased in plasma in IUGR fetuses. Using cultures of fetal muscle progenitor cells (MPCs) we showed reduced myogenic capacity of IUGR compared to NW muscle in vitro, as evidenced by differences in fusion indices and myogenic transcript levels, as well as mTOR activity. Moreover, transfection of MPCs with KLB siRNA promoted myogenesis and mTOR activation, whereas treatment with FGF21 had opposite and dose-dependent effects in porcine and also in human fetal MPCs. In conclusion, our results identify KLB as a novel and potentially critical mediator of impaired muscle development in IUGR, through conserved mechanisms in pigs and humans. Our data sheds new light into the pathogenesis of IUGR, a significant cause of lifelong ill-health in humans and animals. Abstract figure legend In IUGR fetuses, reduced placental supply induces an adaptive response characterized by preferential shunting of blood and therefore oxygen and nutrients to vital tissues such as brain and heart, at the expense of other tissues including skeletal muscle. Using a pig model, we found skeletal muscle from IUGR fetuses to display large-scale gene expression dysregulation including developmental, tissue injury and metabolic genes. Among upregulated genes in IUGR muscle was the FGF21 co-receptor, KLB, whereas FGF21 levels were distinctly elevated in the circulation of IUGR fetuses. Subsequent studies with muscle progenitor cells showed that signaling through FGF21 and KLB inhibits mTOR activation and reduces differentiation and myotube formation by both pig and human cells. These results identify FGF21/KLB signaling as a novel mediator of reduced muscle growth in IUGR fetuses. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Guarda su PubMed
-
Twist regulates Yorkie activity to guide lineage reprogramming of syncytial alary muscles.
Cell Rep2022 Jan;38(4):110295. doi: S2211-1247(22)00001-8.
Rose Marcel, Domsch Katrin, Bartle-Schultheis Jakob, Reim Ingolf, Schaub Christoph,
Abstract
Genesis of syncytial muscles is typically considered as a paradigm for an irreversible developmental process. Notably, transdifferentiation of syncytial muscles is naturally occurring during Drosophila development. The ventral longitudinal heart-associated musculature (VLM) arises by a unique mechanism that revokes differentiation states of so-called alary muscles and comprises at least two distinct steps: syncytial muscle cell fragmentation into single myoblasts and successive reprogramming into founder cells that orchestrate de novo fiber formation of the VLM lineage. Here, we provide evidence that the mesodermal master regulator twist plays a key role during this reprogramming process. Acting downstream of Drosophila Tbx1 (Org-1), Twist is regulating the activity of the Hippo pathway effector Yorkie and is required for the initiation of syncytial muscle dedifferentiation and fragmentation. Subsequently, fibroblast growth factor receptor (FGFR)-Ras-mitogen-activated protein kinase (MAPK) signaling in resulting mononucleated myoblasts maintains Twist expression, thereby stabilizing nuclear Yorkie activity and inducing their lineage switch into founder cells of the VLM.
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Guarda su PubMed
-
Cardiac fibroblast activation detected by Gallium-FAPI-46 positron emission tomography-magnetic resonance imaging as a sign of chronic activity in cardiac sarcoidosis.
Eur Heart J Case Rep2022 Jan;6(1):ytac005. doi: 10.1093/ehjcr/ytac005.
Siebermair Johannes, Kessler Lukas, Kupusovic Jana, Rassaf Tienush, Rischpler Christoph,
Guarda su PubMed
-
Interplay between mineral bone disorder and cardiac damage in acute kidney injury: from Ca mishandling and preventive role of Klotho in mice to its potential mortality prediction in human.
Transl Res2022 Jan;():. doi: S1931-5244(22)00002-0.
González-Lafuente Laura, Navarro-García José Alberto, Rodríguez-Sánchez Elena, Aceves-Ripoll Jennifer, Poveda Jonay, Vázquez-Sánchez Sara, Mercado-García Elisa, Fernández-Velasco María, Kuro-O Makoto, Liaño Fernando, Ruilope Luis M, Ruiz-Hurtado Gema,
Abstract
Biomarkers of mineral bone disorders (MBD) including phosphorus, fibroblast growth factor (FGF)-23 and Klotho are strongly altered in patients with acute kidney injury (AKI) who have high cardiac outcomes and mortality rates. However, the crosslink between MBD and cardiac damage after an AKI episode still remains unclear. We tested MBD and cardiac biomarkers in an experimental AKI model after 24 or 72 hours of folic acid injection and we analyzed structural cardiac remodeling, intracellular calcium (Ca) dynamics in cardiomyocytes and cardiac rhythm. AKI mice presented high levels of FGF-23, phosphorus and cardiac troponin T (cTnT) and exhibited a cardiac hypertrophy phenotype accompanied by an increase in systolic Ca release 24 hours after AKI. Ca transients and contractile dysfunction were reduced 72 hours after AKI while diastolic sarcoplasmic reticulum Ca leak, pro-arrhythmogenic Ca events and ventricular arrhythmias were increased. These cardiac events were linked to the activation of the calcium/calmodulin-dependent kinase II pathway through the increased phosphorylation of ryanodine receptors and phospholamban specific sites after AKI. Cardiac hypertrophy and the altered intracellular Ca dynamics were prevented in transgenic mice overexpressing Klotho after AKI induction. In a translational retrospective longitudinal clinical study, we determined that combining FGF-23 and phosphorus with cTnT levels achieved a better prediction of mortality in AKI patients at hospital admission. Thus, monitoring MBD and cardiac damage biomarkers could be crucial to prevent mortality in AKI patients. In this setting, Klotho might be considered as a new cardioprotective therapeutic tool to prevent deleterious cardiac events in AKI conditions.
Copyright © 2022. Published by Elsevier Inc.
Guarda su PubMed
-
Delivery of modified mRNA to damaged myocardium by systemic administration of lipid nanoparticles.
J Control Release2022 Jan;():. doi: S0168-3659(22)00041-4.
Evers Martijn J W, Du Wenjuan, Yang Qiangbing, Kooijmans Sander A A, Vink Arjan, van Steenbergen Mies, Vader Pieter, de Jager Saskia C A, Fuchs Sabine A, Mastrobattista Enrico, Sluijter Joost P G, Lei Zhiyong, Schiffelers Raymond,
Abstract
Lipid Nanoparticles (LNPs) are a promising drug delivery vehicle for clinical siRNA delivery. Modified mRNA (modRNA) has recently gained great attention as a therapeutic molecule in cardiac regeneration. However, for mRNA to be functional, it must first reach the diseased myocardium, enter the target cell, escape from the endosomal compartment into the cytosol and be translated into a functional protein. However, it is unknown if LNPs can effectively deliver mRNA, which is much larger than siRNA, to the ischemic myocardium. Here, we evaluated the ability of LNPs to deliver mRNA to the myocardium upon ischemia-reperfusion injury functionally. By exploring the bio-distribution of fluorescently labeled LNPs, we observed that, upon reperfusion, LNPs accumulated in the infarct area of the heart. Subsequently, the functional delivery of modRNA was evaluated by the administration of firefly luciferase encoding modRNA. Concomitantly, a significant increase in firefly luciferase expression was observed in the heart upon myocardial reperfusion when compared to sham-operated animals. To characterize the targeted cells within the myocardium, we injected LNPs loaded with Cre modRNA into Cre-reporter mice. Upon LNP infusion, Tdtomato+ cells, derived from Cre mediated recombination, were observed in the infarct region as well as the epicardial layer upon LNP infusion. Within the infarct area, most targeted cells were cardiac fibroblasts but also some cardiomyocytes and macrophages were found. Although the expression levels were low compared to LNP-modRNA delivery into the liver, our data show the ability of LNPs to functionally deliver modRNA therapeutics to the damaged myocardium, which holds great promise for modRNA-based cardiac therapies.
Copyright © 2021. Published by Elsevier B.V.
Guarda su PubMed
-
Medium branched chain fatty acids improve the profile of tricarboxylic acid cycle intermediates in mitochondrial fatty acid ?-oxidation deficient cells: A comparative study.
J Inherit Metab Dis2022 Jan;():. doi: 10.1002/jimd.12480.
Karunanidhi Anuradha, Van't Land Clinton, Rajasundaram Dhivyaa, Grings Mateus, Vockley Jerry, Mohsen Al-Walid,
Abstract
Inherited errors of mitochondrial fatty acid ?-oxidation (FAO) are life threatening, even with optimum care. FAO is the major source of energy for heart and is critical for skeletal muscles especially during physiologic stress. Clinical trials revealed that triheptanoin (commercially known as Dojolvi ; C7G), improved heart function and decreased hypoglycemia in long chain FAO disorders, but other symptoms including rhabdomyolysis persisted, suggesting suboptimal tissue distribution/utilization of heptanoic acid (C7) conjugates and/or rapid liver breakdown. In this study medium branched chain fatty acids were tested as potential anaplerotic treatments in fibroblasts from patients deficient in very long chain acyl-CoA dehydrogenase (VLCAD), long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), trifunctional protein (TFP), and carnitine palmitoyltransferase II (CPT II). Cells were cultured to near confluency and treated with C7, 2,6-dimethylheptanoic acid (dMC7), 6-amino-2,4-dimethylheptanoic acid (AdMC7), or 4,8-dimethylnonanoic acid (dMC9) for 72 hours and targeted metabolomics performed. The profile of TCA cycle intermediates was improved in cells treated with these branched chain fatty acids compared to C7. Intracellular propionate was higher in AdMC7 treated cells compared to C7 in VLCAD, LCHAD, and TFP deficient cell lines. With AdMC7 treatment, succinate was higher in CPT II and VLCAD deficient cells, compared to C7. Malate and glutamate were consistently higher in AdMC7 treated VLCAD, LCHAD, TFP, and CPT II deficient cells compared to the C7 treatment. The results provide the impetus to further evaluate and consider branched chain fatty acids as viable anaplerotic therapy for fatty acid oxidation disorders and other diseases. This article is protected by copyright. All rights reserved.
Copyright © 2022 SSIEM.
Guarda su PubMed
-
Zyxin protects from hypertension-induced cardiac dysfunction.
Cell Mol Life Sci2022 Jan;79(2):93. doi: 10.1007/s00018-022-04133-4.
Al-Hasani Jaafar, Sens-Albert Carla, Ghosh Subhajit, Trogisch Felix A, Nahar Taslima, Friede Prisca A P, Reil Jan-Christian, Hecker Markus,
Abstract
Arterial hypertension causes left ventricular hypertrophy leading to dilated cardiomyopathy. Following compensatory cardiomyocyte hypertrophy, cardiac dysfunction develops due to loss of cardiomyocytes preceded or paralleled by cardiac fibrosis. Zyxin acts as a mechanotransducer in vascular cells that may promote cardiomyocyte survival. Here, we analyzed cardiac function during experimental hypertension in zyxin knockout (KO) mice. In zyxin KO mice, made hypertensive by way of deoxycorticosterone acetate (DOCA)-salt treatment telemetry recording showed an attenuated rise in systolic blood pressure. Echocardiography indicated a systolic dysfunction, and isolated working heart measurements showed a decrease in systolic elastance. Hearts from hypertensive zyxin KO mice revealed increased apoptosis, fibrosis and an upregulation of active focal adhesion kinase as well as of integrins ?5 and ?1. Both interstitial and perivascular fibrosis were even more pronounced in zyxin KO mice exposed to angiotensin II instead of DOCA-salt. Stretched microvascular endothelial cells may release collagen 1?2 and TGF-?, which is characteristic for the transition to an intermediate mesenchymal phenotype, and thus spur the transformation of cardiac fibroblasts to myofibroblasts resulting in excessive scar tissue formation in the heart of hypertensive zyxin KO mice. While zyxin KO mice per se do not reveal a cardiac phenotype, this is unmasked upon induction of hypertension and owing to enhanced cardiomyocyte apoptosis and excessive fibrosis causes cardiac dysfunction. Zyxin may thus be important for the maintenance of cardiac function in spite of hypertension.
© 2022. The Author(s).
Guarda su PubMed
-
Basic fibroblast growth factor inhibits aortic valvular interstitial cells calcification via Notch1 pathway.
J Investig Med2022 Jan;():. doi: jim-2021-002132.
Gao Yuan, Li Ning, Xue Qing, Fan Xinli, Liu Xiaohong, Han Lin,
Abstract
Calcific aortic valve disease (CAVD) is an active pathological process mediated by abnormal activation and transdifferentiation of valvular interstitial cells (VICs). The present study aims to investigate the function and underlying mechanism of the basic fibroblast growth factor (BFGF) on osteogenic differentiation of VICs. Porcine VICs cultured with osteogenic induction medium are supplemented with or without BFGF. Morphology of VICs is identified by fluorescein isothiocyanate-labeled phalloidin, the cell viability is assessed by the cell counting kit-8 method, and protein and mRNA expression level of osteogenic differentiation markers, including Runx2, osteopontin, and Sp7, are verified by western blot analysis and quantitative real-time PCR, respectively. RNA sequencing is used to identify changes in gene profiles. Alizarin Red S staining is used to measure calcium deposition. The results demonstrate that the content of calcium deposition and the expression level of osteogenic markers are downregulated by supplementing BFGF. Notch1 signaling pathway is extracted as a candidate target after bioinformatics analysis by RNA sequencing. The transfection of si-Notch1 abolishes the calcification inhibitory effect of BFGF. Taken together, our findings shed the light on the mechanism and potential therapeutics of BFGF for CAVD.
© American Federation for Medical Research 2022. No commercial re-use. See rights and permissions. Published by BMJ.
Guarda su PubMed
-
Homocysteine promotes cardiac fibrosis by regulating the Akt/FoxO3 pathway.
Ann Transl Med2021 Dec;9(23):1732. doi: 10.21037/atm-21-5602.
Shi Ying, Zhao Lili, Zhang Yifei, Qin Qin, Cong Hongliang, Guo Zhigang,
Abstract
Background:
Evaluated plasma homocysteine (Hcy) is an independent risk factor for cardiac fibrosis which is a common feature of cardiovascular disease, although the mechanisms are still unclear. This study aims to explore the mechanism of Hcy-induced cardiac fibrosis.
Methods:
The mRNA and protein levels of Forkhead box O3 (FoxO3) and differentiation markers were detected in primary cardiac fibroblasts (CFs) after 300 µM Hcy treatment. Scratch and transwell migration assay were used to determine the effect of Hcy on proliferation and migration in CFs. The protein levels involved in the fibrotic processes in mice fed with high methionine diet (HMD) for 4 or 8 weeks were investigated by western blot. CFs were infected with FoxO3 recombinant adenovirus to explore the potential role of FoxO3 in Hcy-induced cardiac dysfunction.
Results:
Hcy treatment significantly promoted the differentiation, proliferation and migration of CFs, while FoxO3 activity were decreased in CFs. In HMD hearts, the protein levels of TIMP1, Fibronectin and ?-SMA were increased after 4 or 8 weeks, but the FoxO3 activity was decreased. Moreover, the HMD hearts had a higher level of Bcl2 but lower of Bax and LC3II protein. In addition, FoxO3 overexpression attenuates Hcy-induced dysfunction in CFs.
Conclusions:
Hcy promotes myofibroblast activation and resistance to autophagy and apoptosis in CFs, and eventually results in cardiac fibrosis by regulating the Akt/FoxO3 pathway. Thus, FoxO3 is a promising therapeutic target to prevent cardiac remodeling.
2021 Annals of Translational Medicine. All rights reserved.
Guarda su PubMed
-
Integrative Analysis of Bulk and Single-Cell RNA Sequencing Data Reveals Cell Types Involved in Heart Failure.
Front Bioeng Biotechnol2021 ;9():779225. doi: 10.3389/fbioe.2021.779225.
Shi Xin, Zhang Li, Li Yi, Xue Jieyuan, Liang Feng, Ni Han-Wen, Wang Xia, Cai Zhaohua, Shen Ling-Hong, Huang Tao, He Ben,
Abstract
Owing to the high mortality rates of heart failure (HF), a more detailed description of the HF becomes extremely urgent. Since the pathogenesis of HF remain elusive, a thorough identification of the genetic factors will provide novel insights into the molecular basis of this cardiac dysfunction. In our research, we performed publicly available transcriptome profiling datasets, including non-failure (NF), dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) hearts tissues. Through principal component analysis (PCA), gene differential expression analysis, gene set enrichment analysis (GSEA), and gene Set Variation Analysis (GSVA), we figured out the candidate genes noticeably altered in HF, the specific biomarkers of endothelial cell (EC) and cardiac fibrosis, then validated the differences of the inflammation-related cell adhesion molecules (CAMs), extracellular matrix (ECM) genes, and immune responses. Taken together, our results suggested the EC and fibroblast could be activated in response to HF. DCM and ICM had both commonality and specificity in the pathogenesis of HF. Higher inflammation in ICM might related to autocrine CCL3/CCL4-CCR5 interaction induced chemokine signaling activation. Furthermore, the activities of neutrophil and macrophage were higher in ICM than DCM. These findings identified features of the landscape of previously underestimated cellular, transcriptomic heterogeneity between ICM and DCM.
Copyright © 2022 Shi, Zhang, Li, Xue, Liang, Ni, Wang, Cai, Shen, Huang and He.
Guarda su PubMed
-
Elevated Serum Fibroblast Growth Factor 21 Is Relevant to Heart Failure Patients with Reduced Ejection Fraction.
Comput Math Methods Med2022 ;2022():7138776. doi: 10.1155/2022/7138776.
Fan Liuzhang, Gu Lingyun, Yao Yuyu, Ma Genshan,
Abstract
Objective:
The aim of this study was to evaluate the roles of fibroblast growth factor 21 (FGF21) in heart failure patients with reduced ejection fraction and its association with Heart Failure with reduced Ejection Fraction (HFrEF).
Methods:
The level of FGF21 was measured by enzyme-linked immunosorbent assay (ELISA) in 199 subjects enrolled in this study, including 128 subjects with HFrEF and 71 control subjects. The mean follow-up time was 13.36 months. The left ventricular end-diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) percentage were evaluated by the 2D echocardiography. Serum brain natriuretic peptide (BNP) was measured in the routine clinical laboratory.
Results:
The serum FGF21 level was evidently higher in patients with HFrEF than in the control group (228.72 ± 24.04 vs. 171.60 ± 12.98,
Conclusion:
FGF21 was independently associated with an increased risk of mortality and readmission HFrEF patients. Therefore, FGF21 has the potential to be a biomarker for the progression of HFrEF in patients.
Copyright © 2022 Liuzhang Fan et al.
Guarda su PubMed
-
Phosphodiesterase-1 in the cardiovascular system.
Cell Signal2022 Jan;():110251. doi: S0898-6568(22)00011-0.
Roks Anton J M,
Abstract
Phosphodiesterases regulate levels of the cyclic nucleotides cyclic adenosine monophosphate and cyclic guanosine monophosphate. Thanks to regulation by specific phosphodiesterase subtypes and isoforms in differential intracellular nanodomains, these versatile, ubiquitous signaling molecules can exert specific effects. This regulation depends on cell type and the (patho)physiological conditions in which these cells reside. In this review phosphodiesterase 1 is highlighted with respect to its structure, function and exploitation as a drug target for modulation of cardiovascular function. The function of its various isoforms in vascular smooth muscle, cardiac myocytes and fibroblasts are discussed. This comprises vasomotor control, cardiac myocyte contractility, growth control, fibrosis and senescence. The conditions that modulate phosphodiesterase 1 and the clinical relevance of this modulation are summarized. These conditions include proliferative status, cell stress, and aging. Furthermore, important associated signaling mechanisms and the implication of nanodomains are described. Also, the prospective of using PDE1 inhibitors as clinical drugs in cardiovascular disease is addressed.
Copyright © 2021. Published by Elsevier Inc.
Guarda su PubMed
-
CREB1 transcription-activated lncRNA PVT1 promotes cardiac fibrosis via miR-145/HCN1 axis.
Int J Cardiol2022 Jan;():. doi: S0167-5273(22)00114-0.
Tian Chengnan, Hu Shuo, Yu Junjian, Li Wentong, Li Peijun, Huang Huanlei,
Abstract
BACKGROUND:
Cardiac fibrosis is a common pathological process of most cardiac diseases, which may result in cardiac function impairment. Long noncoding RNAs (lncRNAs) have been verified as crucial regulators of cardiac fibrosis. This study explored the function and molecular mechanism of PVT1 in cardiac fibrosis.
METHODS:
TGF-?1-exposed human cardiac fibroblasts (HCF-a) and isoproterenol (ISO)-treated mice were used as the in vitro and in vivo cardiac fibrosis models. PVT1, miR-145, and HCN1 expression was determined by quantitative RT-PCR. Cell proliferation was evaluated by CCK-8 and EdU fluorescence staining. ?-SMA and collagen I expression was assessed by immunohistochemical staining and immunofluorescence staining. Protein levels of fibrosis-related factors were assessed by Western blotting. The interaction between miR-145 and PVT1/HCN1 was evaluated by dual luciferase assay. ChIP assay was used to validate the binding of CREB1 to the promoter of PVT1. Cardiac fibrosis in mice was observed by H&E and Masson's trichrome staining.
RESULTS:
PVT1 and HCN1 were up-regulated, while miR-145 was down-regulated in the cardiac fibrosis models. PVT1 knockdown restrained TGF-?1-induced proliferation and activation of HCF-a cells. CREB1 bound to the promoter of PVT1 and activated its transcription. Mechanistically, PVT1 enhanced HCN1 expression via sponging miR-145. Finally, silencing of PVT1 attenuated cardiac fibrosis via regulating miR-145/HCN1 axis in mice in vivo.
CONCLUSION:
PVT1 contributed to cardiac fibrosis by increasing HCN1 expression via sponging miR-145, which suggested that targeting PVT1 may be a therapeutic option for cardiac fibrosis and cardiac diseases.
Copyright © 2022 Elsevier Ireland Ltd. All rights reserved.
Guarda su PubMed
-
Uncaria Rhynchophylla attenuates angiotensin ?-induced myocardial fibrosis via suppression of the RhoA/ROCK1 pathway.
Biomed Pharmacother2022 Feb;146():112607. doi: S0753-3322(21)01394-9.
Xie Lingling, Wang Tianyi, Lin Shan, Lu Zhuqing, Wang Yilian, Shen Zhiqing, Cheng Ying, Shen Aling, Peng Jun, Chu Jianfeng,
Abstract
Uncaria rhynchophylla (UR), a traditional Chinese medicine, has been proven effective in treating hypertensive patients in China. However, the mechanisms of action of UR in reducing hypertension and myocardial fibrosis are still unclear. The purpose of this study was to explore the role of UR in an angiotensin ? (Ang ?) induced mouse model. The mice were randomly divided into 5 groups and infused with Ang ? (500 ng/kg/min) or saline, then administered UR (0.78, 1.56 or 3.12 g/kg/d) or saline for 4 weeks. UR treatment significantly attenuated the elevation of blood pressure caused by Ang ?. It enhanced myocardial function and attenuated the increase in the heart weight index and the pathological changes in the Ang ?-induced hypertensive mice. Furthermore, UR treatment inhibited cardiac fibrosis and significantly down-regulated collagen I, collagen ?, and ?-SMA protein expression in cardiac tissues. UR also attenuated the expression of RhoA, ROCK1, CTGF, and TGF-?1. In cultured cardiac fibroblasts stimulated with Ang ?, UR significantly down-regulated the expression of Collagen I, Collagen III, RhoA, ROCK1, and ?-SMA. In summary, UR can significantly attenuate Ang ?-induced hypertension and cardiac fibrosis, partly via suppression of the RhoA/ROCK1 signaling pathway.
Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
Guarda su PubMed
-
Acellular biomaterial modulates myocardial inflammation and promotes endogenous mechanisms of postinfarct cardiac repair.
J Thorac Cardiovasc Surg2021 Dec;():. doi: S0022-5223(21)01824-9.
Vasanthan Vishnu, Shim Hanjoo B, Teng Guoqi, Belke Darrell, Svystonyuk Daniyil, Deniset Justin F, Fedak Paul W M,
Abstract
OBJECTIVE:
After myocardial infarction, we previously showed that epicardial implantation of porcine small intestinal submucosal extracellular matrix (SIS-ECM) improves postinfarct cardiac function through fibroblast-mediated angiogenic and antifibrotic pathways. Herein, we characterize how SIS-ECM also coordinates a reparative cardiac inflammatory response.
METHODS:
RNA sequencing and multiplex characterized modulation of fibroblast transcriptional and paracrine activity by SIS-ECM. Inhibitors of fibroblast growth factor 2 and toll-like receptor 9 elucidated mechanism. Mice received coronary ligation (infarction) and either SIS-ECM implantation (treatment) or sham surgery (control). Flow cytometry of SIS-ECM and the murine myocardium quantified monocytes, neutrophils, and proangiogenic subtypes. Microscopy tracked fibroblasts and immune cells, and characterized myocardial angiogenesis.
RESULTS:
SIS-ECM increased fibroblast transcription of inflammatory pathways and production of angiogenic vascular endothelial growth factor and inflammatory cytokines via fibroblast growth factor 2 and toll-like receptor 9-dependent pathways. Two-photon microscopy showed that SIS-ECM became engrafted by native fibroblasts and leukocytes, subsequently increasing release of inflammatory cytokines and angiogenic vascular endothelial growth factor. On flow cytometry, SIS-ECM implantation increased day-7 myocardial counts of neutrophils, inflammatory monocytes, and proangiogenic vascular endothelial growth factor recptor 1 subtypes. SIS-ECM has a higher proportion of proangiogenic leukocytes compared with the myocardium. Resonant confocal microscopy showed neovascularization near SIS-ECM.
CONCLUSIONS:
SIS-ECM promotes engraftment by native fibroblasts and leukocytes, and modulates fibroblast activity via fibroblast growth factor 2 and toll-like receptor 9 to potentiate a proangiogenic inflammatory response. Subsequently, the material increases myocardial counts of reparative proangiogenic leukocytes that can induce neovascularization. This reparative inflammatory response may explain previously reported functional improvements. Fibroblast growth factor 2 and toll-like receptor 9 mechanisms can be leveraged to design next-generation materials for postinfarct cardiac repair.
Copyright © 2021 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Guarda su PubMed
-
SPECT and PET Radiotracers in Renal Imaging.
Semin Nucl Med2022 Jan;():. doi: S0001-2998(21)00104-5.
Werner Rudolf A, Pomper Martin G, Buck Andreas K, Rowe Steven P, Higuchi Takahiro,
Abstract
Diuretic scintigraphy includes single-photon emitting radiotracers for planar and single photon emission computed tomography (SPECT) imaging as well as agents for positron emission tomography (PET). These radiotracers provide split-renal functional parameters, including glomerular filtration rate, effective renal plasma flow, tubular function, and/or renal blood flow. Beyond measuring kidney function, the tracer principle also allows for the assessment of various pathophysiological processes in the renal parenchyma, for example ongoing inflammation, activation of angiotensin II type 1 receptor in patients with renovascular hypertension, deterioration of mitochondrial complex I following acute or chronic kidney injury, or characterization of indeterminate renal masses. Providing a whole-body read-out, PET also enables the assessment of kidney-organ interactions, for example cardiorenal crosstalk after primary cardiac injury. This manuscript provides an overview of established clinical applications for single-photon-emitting and PET radiotracers for renal radionuclide imaging. Future perspectives in the field will also be highlighted, such as introduction of PET-guided strategies for drug dose optimization and the recent introduction of radiotracers targeting fibroblast activation protein inhibition, which may allow differentiation between acute inflammatory vs chronic fibrosis in the kidneys.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Guarda su PubMed
-
Mast cells and basic fibroblast growth factor in physiological aging of rat heart and kidney.
Biotech Histochem2022 Jan;():1-15. doi: 10.1080/10520295.2021.2024251.
Stamenov Nikola, Kotov Georgi, Iliev Alexandar, Landzhov Boycho, Kirkov Vidin, Stanchev Stancho,
Abstract
Age-related morphological and physiological changes occur in cells, tissues and organs with high metabolic or mitotic activity; these changes decrease their regenerative capacity. One such change is interstitial fibrosis. Mast cells contain basic fibroblast growth factor and have been related to pro-fibrotic activity. We investigated the role of mast cells in physiological aging of the heart and kidney. We analyzed changes in mast cell number and compared the left and right heart ventricles and kidneys of 6- and 12-month-old Wistar rats. We also evaluated the immunohistochemical expression of basic fibroblast growth factor. Finally, we analyzed changes in the extent of interstitial fibrosis and in the glomerular sclerosis index as nonspecific markers of aging and correlated these parameters with of mast cells. Mast cells were visualized by toluidine blue staining and specific immunohistochemical expression of tryptase. The expression of basic fibroblast growth factor was assessed semiquantitatively. The extent of interstitial fibrosis was investigated using Mallory's trichrome staining. Glomerular sclerosis was evaluated using periodic acid-Schiff staining. We found that the number of mast cells increased significantly in the older rats. We also found that the number of mast cells was greatest in the left ventricle followed by the right ventricle, then the kidney. The immunoreactivity of basic fibroblast growth factor also increased in older animals. Correlations between the number of mast cells and immunoreactivity of basic fibroblast growth factor, extent of interstitial fibrosis and glomerular sclerosis index demonstrated the association between mast cells and age-related tissue remodeling of the heart and kidney.
Guarda su PubMed
-
Polyphosphazene-Based Nanocarriers for the Release of Camptothecin and Epirubicin.
Pharmaceutics2022 Jan;14(1):. doi: 169.
Quiñones Javier Pérez, Roschger Cornelia, Iturmendi Aitziber, Henke Helena, Zierer Andreas, Peniche-Covas Carlos, Brüggemann Oliver,
Abstract
The design and study of efficient polymer-based drug delivery systems for the controlled release of anticancer drugs is one of the pillars of nanomedicine. The fight against metastatic and invasive cancers demands therapeutic candidates with increased and selective toxicity towards malignant cells, long-term activity and reduced side effects. In this sense, polyphosphazene nanocarriers were synthesized for the sustained release of the anticancer drugs camptothecin (CPT) and epirubicin (EPI). Linear poly(dichloro)phosphazene was modified with lipophilic tocopherol or testosterone glycinate, with antioxidant and antitumor activity, and with hydrophilic Jeffamine M1000 to obtain different polyphosphazene nanocarriers. It allowed us to encapsulate the lipophilic CPT and the more hydrophilic EPI. The encapsulation process was carried out via solvent exchange/precipitation, attaining a 9.2-13.6 wt% of CPT and 0.3-2.4 wt% of EPI. CPT-loaded polyphosphazenes formed 140-200 nm aggregates in simulated body physiological conditions (PBS, pH 7.4), resulting in an 80-100-fold increase of CPT solubility. EPI-loaded polyphosphazenes formed 250 nm aggregates in an aqueous medium. CPT and EPI release (PBS, pH 7.4, 37 °C) was monitored for 202 h, being almost linear during the first 8 h. The slow release of testosterone and tocopherol was also sustained for 150 h in PBS (pH 7.4 and 6.0) at 37 °C. The co-delivery of testosterone or tocopherol and the anticancer drugs from the nanocarriers was expected. Cells of the human breast cancer cell line MCF-7 demonstrated good uptake of anticancer-drug-loaded nanocarriers after 6 h. Similarly, MCF-7 spheroids showed good uptake of the anticancer-drug-loaded aggregates after 72 h. Almost all anticancer-drug-loaded polyphosphazenes exhibited similar or superior toxicity against MCF-7 cells and spheroids when compared to raw anticancer drugs. Additionally, cell-cycle arrest in the G2/M phase was increased in response to the drug-loaded nanocarriers. Almost no toxicity of anticancer-drug-loaded aggregates against primary human lung fibroblasts was observed. Furthermore, the aggregates displayed no hemolytic activity, which is in contrast to the parent anticancer drugs. Consequently, synthesized polyphosphazene-based nanocarriers might be potential nanomedicines for chemotherapy.
Guarda su PubMed
-
Common and Distinctive Intercellular Communication Patterns in Human Obstructive and Nonobstructive Hypertrophic Cardiomyopathy.
Int J Mol Sci2022 Jan;23(2):. doi: 946.
Codden Christina J, Chin Michael T,
Abstract
Hypertrophic Cardiomyopathy (HCM) is a common inherited disorder characterized by unexplained left ventricular hypertrophy with or without left ventricular outflow tract (LVOT) obstruction. Single-nuclei RNA-sequencing (snRNA-seq) of both obstructive and nonobstructive HCM patient samples has revealed alterations in communication between various cell types, but no direct and integrated comparison between the two HCM phenotypes has been reported. We performed a bioinformatic analysis of HCM snRNA-seq datasets from obstructive and nonobstructive patient samples to identify differentially expressed genes and distinctive patterns of intercellular communication. Differential gene expression analysis revealed 37 differentially expressed genes, predominantly in cardiomyocytes but also in other cell types, relevant to aging, muscle contraction, cell motility, and the extracellular matrix. Intercellular communication was generally reduced in HCM, affecting the extracellular matrix, growth factor binding, integrin binding, PDGF binding, and SMAD binding, but with increases in adenylate cyclase binding, calcium channel inhibitor activity, and serine-threonine kinase activity in nonobstructive HCM. Increases in neuron to leukocyte and dendritic cell communication, in fibroblast to leukocyte and dendritic cell communication, and in endothelial cell communication to other cell types, largely through changes in the expression of integrin-?1 and its cognate ligands, were also noted. These findings indicate both common and distinct physiological mechanisms affecting the pathogenesis of obstructive and nonobstructive HCM and provide opportunities for the personalized management of different HCM phenotypes.
Guarda su PubMed
-
Antibodies against Angiotensin II Type 1 and Endothelin 1 Type A Receptors in Cardiovascular Pathologies.
Int J Mol Sci2022 Jan;23(2):. doi: 927.
Civieri Giovanni, Iop Laura, Tona Francesco,
Abstract
Angiotensin II receptor type 1 (AT1R) and endothelin-1 receptor type A (ETAR) are G-protein-coupled receptors (GPCRs) expressed on the surface of a great variety of cells: immune cells, vascular smooth cells, endothelial cells, and fibroblasts express ETAR and AT1R, which are activated by endothelin 1 (ET1) and angiotensin II (AngII), respectively. Certain autoantibodies are specific for these receptors and can regulate their function, thus being known as functional autoantibodies. The function of these antibodies is similar to that of natural ligands, and it involves not only vasoconstriction, but also the secretion of proinflammatory cytokines (such as interleukin-6 (IL6), IL8 and TNF-?), collagen production by fibroblasts, and reactive oxygen species (ROS) release by fibroblasts and neutrophils. The role of autoantibodies against AT1R and ETAR (AT1R-AAs and ETAR-AAs, respectively) is well described in the pathogenesis of many medical conditions (e.g., systemic sclerosis (SSc) and SSc-associated pulmonary hypertension, cystic fibrosis, and allograft dysfunction), but their implications in cardiovascular diseases are still unclear. This review summarizes the current evidence regarding the effects of AT1R-AAs and ETAR-AAs in cardiovascular pathologies, highlighting their roles in heart transplantation and mechanical circulatory support, preeclampsia, and acute coronary syndromes.
Guarda su PubMed
