Abstract P317: Cardiac Fibroblast GSK3α Promotes Myocardial Fibrotic Remodeling Through GSK3α-ERK-IL11 Signaling Circuit

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Prachi Umbarkar ◽  
Sultan Tousif ◽  
Anand P Singh ◽  
Joshua C Anderson ◽  
qinkun zhang ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Critical Role ◽  
Flow Cytometric Analysis ◽  
Collagen Gel ◽  
Pressure Overload ◽  
Negative Regulator ◽  
Post Injury

Background: Myocardial fibrosis contributes significantly to heart failure (HF). Fibroblasts are among the predominant cell type in the heart and are primary drivers of fibrosis. To identify the kinases involved in fibrosis, we analyzed the kinome of mouse cardiac fibroblasts (CF) isolated from normal and failing hearts. This unbiased screening revealed the critical role of the GSK-3 family-centric pathways in fibrosis. Previously we have shown that among two isoforms of GSK3, CF-GSK3β acts as a negative regulator of fibrosis in the injured heart. However, the role of CF-GSK3α in the pathogenesis of cardiac diseases is completely unknown. Methods and Results: To define the role of CF-GSK3α in HF, we employed two novel fibroblast-specific KO mouse models. Specifically, GSK3α was deleted from fibroblasts or myofibroblasts with tamoxifen-inducible Tcf21- or periostin- promoter-driven Cre recombinase. In both models, GSK3α deletion restricted pressure overload-induced cardiac fibrosis and preserved cardiac function. We examined the effect of GSK3α deletion on myofibroblast transformation and pro-fibrotic TGFβ1-SMAD3 signaling in vitro . A significant reduction in cell migration, collagen gel contraction, and α-SMA expression in TGFβ1-treated KO CFs confirmed that GSK3α is required for myofibroblast transformation. Surprisingly, GSK3α deletion did not affect SMAD3 activation, indicating the pro-fibrotic role of GSK3α is SMAD3 independent. To further delineate the underlying mechanisms, proteins were isolated from CFs of WT and KO mice at 4 weeks post-injury, and kinome profiling was performed. The kinome analysis identified the downregulation of RAF family kinase activity in KO CFs. Moreover, mapping of significantly altered kinases against literature annotated interactions generated ERK-centric networks. Consistently, flow cytometric analysis of CFs confirmed significantly low levels of pERK in KO mice. Additionally, our in vitro studies demonstrated that GSK3α deletion prevents TGFβ1-induced ERK activation. Interestingly, IL-11, a pro-fibrotic downstream effector of TGFβ1, was remarkably reduced in KO CFs and ERK inhibition further decreased IL-11 expression. Taken together, herein, we discovered the GSK3α-ERK-IL-11 signaling as a critical pro-fibrotic pathway in the heart. Strategies to inhibit this pro-fibrotic network could prevent adverse fibrosis and HF. Conclusion: CF-GSK3α plays a causal role in myocardial fibrosis that could be therapeutically targeted for future clinical applications.

scholarly journals Cardiac fibroblast GSK-3α mediates adverse myocardial fibrosis via IL-11 and ERK pathway

2021 ◽  
Author(s):  
Prachi Umbarkar ◽  
Sultan Tousif ◽  
Anand P. Singh ◽  
Joshua C. Anderson ◽  
Qinkun Zhang ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Glycogen Synthase ◽  
Cardiac Injury ◽  
Flow Cytometric Analysis ◽  
Cardiac Fibroblast ◽  
Negative Regulator ◽  
Erk Pathway ◽  
Post Injury

AbstractBackgroundHeart failure is the leading cause of mortality, morbidity, and healthcare expenditures worldwide. Numerous studies have implicated Glycogen Synthase Kinase-3 (GSK-3) as a promising therapeutic target for cardiovascular diseases. GSK-3 isoforms appear to play overlapping, unique, and even opposing functions in the heart. Recently our group has identified cardiac fibroblast (CF) GSK-3β as a negative regulator of fibrotic remodeling in the ischemic heart. However, the role of CF-GSK-3α in myocardial fibrosis is unknown.Methods and ResultsHerein, we employed two entirely novel conditional fibroblast-specific and tamoxifen-inducible mouse models to define the role of CF-GSK-3α in fibroblast activation and myocardial fibrosis. Specifically, GSK-3α was deleted from cardiac fibroblasts or myofibroblasts with tamoxifen-inducible Tcf21- or periostin-promoter-driven Cre recombinase. At 2 months of age, WT and KO mice were subjected to cardiac injury, and heart functions were monitored by serial echocardiography. Histological analysis and morphometric studies were performed at 8 weeks post-injury. In both settings, GSK-3α deletion restricted fibrotic remodeling and improved cardiac function. To investigate underlying mechanisms, we examined the effect of GSK-3α deletion on myofibroblast transformation and pro-fibrotic TGFβ1-SMAD3 signaling in vitro. A significant reduction in cell migration, collagen gel contraction, and α-SMA expression in TGFβ1 treated GSK-3α KO MEFs confirmed that GSK-3α is required for myofibroblast transformation. Surprisingly, GSK-3α deletion did not affect SMAD3 activation, indicating the pro-fibrotic role of GSK-3α is SMAD3 independent. To further delineate the underlying mechanism, total proteins were isolated from CFs of WT and KO animals at 4 weeks post-injury, and kinome profiling was performed by utilizing PamStation®12 high throughput microarray platform. The kinome analysis identified the downregulation of RAF family kinase activity in GSK3α-KO-CFs. Moreover, mapping of significantly altered kinases against literature annotated interactions generated ERK-centric networks. Importantly, flow cytometric analysis of CFs confirmed a significant decrease in pERK levels in KO mice. Additionally, our in vitro studies demonstrated that GSK-3α deletion prevented TGFβ1 induced ERK activation thereby validating our findings from kinome analysis. Interestingly, IL-11, a fibroblast specific downstream effector of TGFβ1, was very low in GSK-3α KO MEFs as compared to WT and ERK inhibition further reduced IL-11 expression in them. All these results indicate that GSK-3α mediates pro-fibrotic response in the injured heart through IL-11 and ERK pathway.ConclusionCF-GSK-3α plays a causal role in myocardial fibrosis that could be therapeutically targeted for future clinical applications.

Abstract 285: High Throughput Profiling of Gsk3α Regulated Fibroblast Kinome Reveals Raf as a Mediator of Fibrosis in Failing Heart

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Prachi Umbarkar ◽  
Sultan Tousif ◽  
Anand P Singh ◽  
Joshua C Anderson ◽  
Qinkun Zhang ◽  
...  
Keyword(s):  
High Throughput ◽  
Glycogen Synthase ◽  
Cardiac Injury ◽  
Collagen Gel ◽  
Microarray Platform ◽  
Negative Regulator ◽  
Post Injury ◽  
Cardiac Pathophysiology

Background: Heart failure is the leading cause of mortality, morbidity, and healthcare expenditures worldwide. Numerous studies have implicated Glycogen Synthase Kinase-3 (GSK-3) as a promising therapeutic target for cardiovascular diseases. GSK-3 isoforms appear to play overlapping, unique, and even opposing functions in the heart. Recently our group has identified cardiac fibroblast (CF) GSK3β as a negative regulator of fibrotic remodeling in the ischemic heart. However, the role of CF-GSK3α in cardiac pathophysiology is unknown. Methods and Results: GSK3α was deleted specifically from cardiac fibroblasts or myofibroblasts with tamoxifen-inducible TCF21- or periostin- promoter-driven Cre recombinase. At 2 months of age, WT and KO mice were subjected to cardiac injury, and heart functions were monitored by serial echocardiography. Histological analysis and morphometric studies were performed at 8 weeks post-injury. In both settings, GSK3α deletion restricted fibrotic remodeling and improved cardiac function. To investigate underlying mechanisms, we examined the effect of GSK3α deletion on myofibroblast transformation and pro-fibrotic TGFβ1-SMAD3 signaling in vitro . WT and KO mouse embryonic fibroblasts (MEFs) were treated with TGFβ1. Indeed, a significant reduction in cell migration, collagen gel contraction, and α-SMA expression in TGFβ1 treated KO MEFs confirmed that GSK3α is required for myofibroblast transformation. Surprisingly, GSK3α deletion had no effect on SMAD3 activation, indicating the pro-fibrotic role of GSK3α is SMAD3 independent. At 4 weeks post-injury, total proteins were isolated from CFs of WT and KO animals, and kinome profiling was performed by utilizing PamStation®12 high throughput microarray platform. The upstream kinase analysis identified the downregulation of RAF family kinase activity in GSK3α-KO-CFs. Moreover, mapping of significantly altered kinases against literature annotated interactions generated ERK-centric networks. These findings are consistent with previous studies that implicated ERK in fibrotic diseases across multiple organs. Conclusion: CF-GSK3α plays a causal role in the cardiac pathophysiology that could be therapeutically targeted for future clinical applications.

scholarly journals MicroRNA-150 Inhibits the Activation of Cardiac Fibroblasts by Regulating c-Myb

2016 ◽  
Vol 38 (6) ◽  
pp. 2103-2122 ◽  
Author(s):  
Peng Deng ◽  
Ling Chen ◽  
Zheng Liu ◽  
Ping Ye ◽  
Sihua Wang ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Cardiac Function ◽  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Heart Cell ◽  
Factor C

Background/Aims: Cardiac fibrosis is the primary cause of deteriorated cardiac function in various cardiovascular diseases. Numerous studies have demonstrated that microRNAs (miRNAs) are critical regulators of myocardial fibrosis. Specifically, many studies have reported that miR-150 is downregulated in cardiovascular diseases, such as acute myocardial infarction (AMI), myocardial hypertrophy and myocardial fibrosis. However, the exact role of miR-150 in these pathological processes remains unknown. Methods: We used the transverse aortic constriction (TAC) mouse model to study the role of miR-150 in cardiac fibrosis induced by pressure overload. After the TAC operation, qRT-PCR was used to measure the expression profiles of miR-150 in left ventricle tissues and populations of primary heart cell types. Then, we used both miR-150 knockout mice and wild type (WT) mice in the TAC model. Changes in cardiac function and pathology were measured using transthoracic echocardiography and pathological analysis, respectively. Furthermore, we predicted the target of miR-150 in cardiac fibroblasts (CFs) and completed in vitro CF transfection experiments using miR-150 analogs and siRNA corresponding to the predicted target. Results: We observed decreased expression levels of miR-150 in hearts suffering pressure overload, and these levels decreased more sharply in CFs than in cardiomyocytes. In addition, the degrees of cardiac function deterioration and cardiac fibrosis in miR-150-/- mice were more severe than were those in WT mice. By transfecting CFs with an miR-150 analog in vitro, we observed that miR-150 inhibited cardiac fibroblast activation. We predicted that the transcription factor c-Myb was the target of miR-150 in CFs. Transfecting CFs with c-Myb siRNA eliminated the effects of an miR-150 inhibitor, which promoted CF activation. Conclusion: These findings reveal that miR-150 acts as a pivotal regulator of pressure overload-induced cardiac fibrosis by regulating c-Myb.

Abstract 026: Role of Tank in the Regulation of Pathological Cardiac Hypertrophy

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Hongliang Li ◽  
Peng Zhang
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Adaptor Protein ◽  
Negative Regulator ◽  
Akt Inhibitor ◽  
Aortic Banding ◽  
Pathological Cardiac Hypertrophy

TRAF associated NF-κB activator (TANK) is adaptor protein which was identified as a negative regulator of TRAF-, TBK1- and IKKi-mediated signal transduction through its interaction with them. Besides its important roles in the regulation of immune response, it has been reported that TANK contributes to the development of autoimmune nephritis and osteoclastogenesis. However, its functions in cardiovascular diseases especially cardiac hypertrophy is largely unknown. In the present study, we interestingly observed that TNAK expression is increased by 240% in human hypertrophic cardiomyopathy(HCM)tissue and 320% in mouse hypertrophic heart after aortic banding (AB), indicating that TANK may be involved in the pathogenesis of this diseases. Subsequently, cardiac-specific TANK knockout (TANK-KO) and transgenic(TANK-TG)mice were generated and subjected to AB for 4 to 8 weeks. Our results demonstrated that TANK deficiency prevented against cardiac hypertrophy and fibrosis induced by pressure overload,as evidenced by that the cardiomyocytes enlargement and fibrosis formation was reduced by about 34% and 43% compared with WT mice, respectively. Conversely, TANK-TG mice showed an aggravated effect on cardiac hypertrophy in response to pressure overload with 36% and 47% increase of cardiomyocytes enlargement and fibrosis formation compared with non-transgenic mice. More importantly, in vitro experiments further revealed that TANK overexpression which was mediated by adenovirus in the cardiomyocytes dramatically increased the cell size and the expression of hypertrophic markers, whereas TANK knockdown had an opposite function. Mechanistically, we discovered that AKT signaling was activated (230%) in the hearts of TANK-TG mice, while being greatly reduced in TNAK-KO hearts after aortic banding. Moreover, blocking AKT/GSK3β signaling with a pharmacological AKT inhibitor reversed cardiac dysfunction of TANK-TG mice. Collectively, our data show that TNAK acts as a novel regulator of pathological cardiac hypertrophy and may be a promising therapeutic targets.

Adenovirus Induced Thrombocytopenia: The Role of P-Selectin and von Willebrand Factor in Virus- Mediated Platelet Clearance.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 222-222 ◽  
Author(s):  
Maha Othman ◽  
Andrea Labelle ◽  
Ian Mazzetti ◽  
David Lillicrap
Keyword(s):  
Platelet Activation ◽  
Von Willebrand Factor ◽  
Critical Role ◽  
Flow Cytometric Analysis ◽  
Adhesive Proteins ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Acute thrombocytopenia has been consistently reported following IV administration of adenoviral vectors (Ad) but the mechanism responsible for this phenomenon has not been elucidated. Thrombocytopenia appears 24 hours after IV administration of Ad and is vector dose dependent. In this study, we have assessed the potential roles of the adhesive proteins P-selectin and von Willebrand Factor (VWF) on the aggregation and clearance of platelets following virus administration. We have addressed the question of whether the thrombocytopenia is due to a direct effect of the virus on platelets or an indirect effect related to interaction of platelets with other proteins or cells modified by the virus. We assessed platelet count in a group of Balb/c and C57Bl/6 mice over 1 week period following Ad administration and performed a detailed examination of the events within the first 24 h after Ad injection, the period that precedes the appearance of thrombocytopenia. We examined the effect of Ad on expression of the platelet activation marker P-selectin and the formation of platelet leukocyte aggregates (PLA) by means of flowcytometry after incubation of adenovirus with mouse platelets in vitro, and following Ad administration in vivo. To assess the role of VWF in Ad-induced thrombocytopenia we measured plasma VWF levels one hour after injection of Ad. Further investigations involved comparison of platelet counts, platelet activation, and the formation of PLA in a group of VWF KO mice. All studies have been performed with a replication deficient E1/E3-deleted Ad 1x 1011 viral particles/mouse. Our in vitro studies have shown that Ad directly activates mouse platelets as shown by increased expression of P-selectin. The average index of platelet activation for platelets stimulated by Ad was 2519.4 compared to 128.2 for resting platelets (n=5, p<0.02). Flow cytometric analysis of CD41 (platelets) and CD45 (leucocytes) double stained positive events indicated that Ad stimulation induced PLA when compared to the unstimulated samples. Our in vivo studies have confirmed the development of significant thrombocytopenia in both Balb/c as well as C57Bl/6 WT mice (n=8, p=0.00001, n= 6, p=0.002) 24 hours following Ad administration. Significant P-selectin expression was documented in both strains (n=4,p=0.0003; n=3, p=0.0008 respectively) as well as significant PLA one hour following Ad (n=4, p=0.01; n=3, p=0.007). The VWF KO mice showed non-significant thrombocytopenia (n= 6, p=0.063) at 24 hours following Ad, significant P-selectin expression (n=3, p=0.0003), but no significant PLA formation at one hour (n=3 p=0.12) relative to pre-injection levels. Plasma VWF levels were significantly elevated in both Balb/c and C57Bl/6 WT mice one hour following administration of the virus (n= 3, p=0.02; n= 3, p= 0.001). The average plasma VWF levels were 48.1 U/mL at 1h compared to 5.7 U/mL pre injection in Balb /c mice and 85.9 U/mL compared to 6.1 U/mL in C57Bl/6 mice. These studies have shown that Ad can act as an inducer of mouse platelet activation and as a promoter for platelet-leukocyte association both in vitro and in vivo. We have demonstrated a role for Ad in stimulating VWF release from the endothelium, and have shown that VWF has a critical role in platelet activation and clearance following Ad administration. We conclude that P-selectin and VWF proteins are directly involved in interactions between endothelial cells, platelets and leukocytes, a complex interaction that can explain at least in part the mechanisms underlying Ad-mediated thrombocytopenia.

scholarly journals Genetic ablation of Cullin-RING E3 ubiquitin ligase 7 restrains pressure overload-induced myocardial fibrosis

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244096
Author(s):  
Melanie Anger ◽  
Florian Scheufele ◽  
Deepak Ramanujam ◽  
Kathleen Meyer ◽  
Hidehiro Nakajima ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Ubiquitin Ligase ◽  
Cardiac Fibrosis ◽  
E3 Ubiquitin Ligase ◽  
Pressure Overload ◽  
Negative Regulator ◽  
Apoptotic Cells ◽  
Specific Expression ◽  
Genetic Ablation ◽  
Ring E3

Fibrosis is a pathognomonic feature of structural heart disease and counteracted by distinct cardioprotective mechanisms, e.g. activation of the phosphoinositide 3-kinase (PI3K) / AKT pro-survival pathway. The Cullin-RING E3 ubiquitin ligase 7 (CRL7) was identified as negative regulator of PI3K/AKT signalling in skeletal muscle, but its role in the heart remains to be elucidated. Here, we sought to determine whether CRL7 modulates to cardiac fibrosis following pressure overload and dissect its underlying mechanisms. For inactivation of CRL7, the Cullin 7 (Cul7) gene was deleted in cardiac myocytes (CM) by injection of adeno-associated virus subtype 9 (AAV9) vectors encoding codon improved Cre-recombinase (AAV9-CMV-iCre) in Cul7flox/flox mice. In addition, Myosin Heavy Chain 6 (Myh6; alpha-MHC)-MerCreMer transgenic mice with tamoxifen-induced CM-specific expression of iCre were used as alternate model. After transverse aortic constriction (TAC), causing chronic pressure overload and fibrosis, AAV9-CMV-iCre induced Cul7-/- mice displayed a ~50% reduction of interstitial cardiac fibrosis when compared to Cul7+/+ animals (6.7% vs. 3.4%, p<0.01). Similar results were obtained with Cul7flox/flox Myh6-Mer-Cre-MerTg(1/0) mice which displayed a ~30% reduction of cardiac fibrosis after TAC when compared to Cul7+/+ Myh6-Mer-Cre-MerTg(1/0) controls after TAC surgery (12.4% vs. 8.7%, p<0.05). No hemodynamic alterations were observed. AKTSer473 phosphorylation was increased 3-fold (p<0.01) in Cul7-/- vs. control mice, together with a ~78% (p<0.001) reduction of TUNEL-positive apoptotic cells three weeks after TAC. In addition, CM-specific expression of a dominant-negative CUL71152stop mutant resulted in a 16.3-fold decrease (p<0.001) of in situ end-labelling (ISEL) positive apoptotic cells. Collectively, our data demonstrate that CM-specific ablation of Cul7 restrains myocardial fibrosis and apoptosis upon pressure overload, and introduce CRL7 as a potential target for anti-fibrotic therapeutic strategies of the heart.

Integrin α2β1 (VLA-2) is a principal receptor used by neutrophils for locomotion in extravascular tissue

Blood ◽  
2000 ◽  
Vol 95 (5) ◽  
pp. 1804-1809 ◽  
Author(s):  
Joachim Werr ◽  
Joakim Johansson ◽  
Einar E. Eriksson ◽  
Per Hedqvist ◽  
Erkki Ruoslahti ◽  
...  
Keyword(s):  
Laser Scanning ◽  
Critical Role ◽  
Collagen Gel ◽  
Time Lapse ◽  
Surface Expression ◽  
Laser Scanning Confocal Microscopy ◽  
Rat Mesentery

Cell adhesion molecules are critically involved in the multistep process of leukocyte recruitment in inflammation. The specific receptors used by polymorphonuclear leukocytes (PMN) for locomotion in extravascular tissue have as yet not been identified. By means of immunofluorescence flow cytometry and laser scanning confocal microscopy, this study demonstrated that surface expression of the 2β1 (VLA-2) integrin, though absent on blood PMN, is induced in extravasated PMN collected from human skin blister chambers, and rat PMN accumulated in the peritoneal cavity after chemotactic stimulation. Intravital time-lapse videomicroscopy was used to investigate chemoattractant-induced PMN locomotion in the rat mesentery in vivo. Local administration of function-blocking monoclonal antibody or peptide recognizing the 2β1 integrin reduced PMN migration velocity in the extravascular tissue by 73% ± 3% and 70% ± 10%, respectively ( means ± SD). The distance f-met-leu-phe peptide (fMLP)-stimulated human PMN migrated in a collagen gel in vitro was markedly reduced by treatment with anti-2 mAbs or peptide, whereas no effect was observed with antibodies or peptides recognizing the 4β1 or 5β1integrins. Further evidence for a critical role of expression of 2β1 integrin in PMN locomotion in extravascular tissue was obtained in the mouse air pouch model of acute inflammation where chemoattractant-induced PMN recruitment was substantially inhibited by local anti-2 mAb treatment. Thus, expression of 2β1 integrin on extravasated PMN has been identified and a novel role of this receptor in regulating the extravascular phase of leukocyte trafficking in inflammation has been formulated.

scholarly journals The Critical Role of Scleraxis in Pressure Overload‐Induced Cardiac Fibrosis

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Raghu Sundaresan Nagalingam ◽  
David Yat‐Chung Cheung ◽  
Nina Aroutiounova ◽  
Davinder S. Jassal ◽  
Michael Paul Czubryt
Keyword(s):  
Cardiac Fibrosis ◽  
Critical Role ◽  
Pressure Overload

Abstract 410: Rhein Administration Prevents Cardiac Fibrosis by Interfering with the TGF-β Pathway

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
David Barbosa ◽  
Melanie Wehmöller ◽  
Maximilian R Spinner ◽  
Ulrich Rüther ◽  
Margriet Ouwens
Keyword(s):  
Cardiac Fibrosis ◽  
Heart Function ◽  
Cardiac Fibroblasts ◽  
Heart Diseases ◽  
Collagen Gel ◽  
Pressure Overload ◽  
Protein Levels ◽  
Adverse Remodeling

Fibrosis, which occurs in various heart diseases like acute myocardial ischemia and pressure overload, is triggered by the differentiation of fibroblasts into myofibroblasts. Dysregulation of this reparative mechanism results in excessive collagen accumulation leading to cardiac stiffness and impaired heart function. The aim of this study was to determine whether the rhubarb anthraquinone Rhein, a drug already used as treatment for chondroarthritis, prevents the transdifferentiation of cardiac fibroblasts. We observed that Rhein pre-treatment ameliorates the cardiac function and reduces adverse remodeling after acute myocardial infarction in mice, in vivo . In primary human cardiac fibroblasts, Rhein incubation dose-dependently inhibited the TGF-β-mediated upregulation of α-SMA, the master marker for myofibrolasts, and prevented the contraction of fibroblast-populated collagen gel lattices upon TGF-β stimulation. Further, Rhein reduced TGFβ-R1 expression in primary human cardiac fibroblast, resulting in decreased SMAD2 phosphorylation and blunting of the fibrogenic response. Furthermore, Rhein stabilized protein levels of SMAD7, a key inhibitor of TGF-β signaling. Collectively, these data show for the first time that Rhein administration prevents cardiac fibrosis in vivo and in vitro by blunting the TGF-β signaling pathway, and identify Rhein as potential therapeutic treatment to prevent excessive fibrosis and adverse remodeling in cardiac pathologies.

scholarly journals NLRP7 Promotes Choriocarcinoma Growth and Progression through the Establishment of an Immunosuppressive Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2999
Author(s):  
Deborah Reynaud ◽  
Roland Abi Nahed ◽  
Nicolas Lemaitre ◽  
Pierre-Adrien Bolze ◽  
Wael Traboulsi ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Cells ◽  
Major Gene ◽  
Critical Role ◽  
Orthotopic Model ◽  
Independent Manner ◽  
Maternal Immune Response ◽  
The Impact

The inflammatory gene NLRP7 is the major gene responsible for recurrent complete hydatidiform moles (CHM), an abnormal pregnancy that can develop into gestational choriocarcinoma (CC). However, the role of NLRP7 in the development and immune tolerance of CC has not been investigated. Three approaches were employed to define the role of NLRP7 in CC development: (i) a clinical study that analyzed human placenta and sera collected from women with normal pregnancies, CHM or CC; (ii) an in vitro study that investigated the impact of NLRP7 knockdown on tumor growth and organization; and (iii) an in vivo study that used two CC mouse models, including an orthotopic model. NLRP7 and circulating inflammatory cytokines were upregulated in tumor cells and in CHM and CC. In tumor cells, NLRP7 functions in an inflammasome-independent manner and promoted their proliferation and 3D organization. Gravid mice placentas injected with CC cells invalidated for NLRP7, exhibited higher maternal immune response, developed smaller tumors, and displayed less metastases. Our data characterized the critical role of NLRP7 in CC and provided evidence of its contribution to the development of an immunosuppressive maternal microenvironment that not only downregulates the maternal immune response but also fosters the growth and progression of CC.

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