scholarly journals Glycolysis Inhibition Alleviates Cardiac Fibrosis After Myocardial Infarction by Suppressing Cardiac Fibroblast Activation

2021 ◽  
Vol 8 ◽  
Author(s):  
Zhi-Teng Chen ◽  
Qing-Yuan Gao ◽  
Mao-Xiong Wu ◽  
Meng Wang ◽  
Run-Lu Sun ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Western Blot ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblast ◽  
Rank Test ◽  
Fluorescence Signal ◽  
Fibroblast Activation ◽  
Log Rank Test ◽  
Masson Staining

Objective: To explore the role of glycolysis in cardiac fibroblast (CF) activation and cardiac fibrosis after myocardial infarction (MI).Method:In vivo: 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor, was injected into the abdominal cavity of the MI or sham mice every day. On the 28th day, cardiac function was measured by ultrasonic cardiography, and the hearts were harvested. Masson staining and immunofluorescence (IF) were used to evaluate the fibrosis area, and western blot was used to identify the glycolytic level. In vitro, we isolated the CF from the sham, MI and MI with 2-DG treatment mice, and we also activated normal CF with transforming growth factor-β1 (TGF-β1) and block glycolysis with 2-DG. We then detected the glycolytic proteins, fibrotic proteins, and the concentrations of lactate and glucose in the culture medium. At last, we further detected the fibrotic and glycolytic markers in human fibrotic and non-fibrotic heart tissues with masson staining, IF and western blot.Result: More collagen and glycolytic protein expressions were observed in the MI mice hearts. The mortality increased when mice were treated with 2-DG (100 mg/kg/d) after the MI surgery (Log-rank test, P < 0.05). When the dosage of 2-DG declined to 50 mg/kg/d, and the treatment was started on the 4th day after MI, no statistical difference of mortality between the two groups was observed (Log-rank test, P = 0.98). The collagen volume fraction was smaller and the fluorescence signal of α-smooth muscle actin (α-SMA) was weaker in mice treated with 2-DG than PBS. In vitro, 2-DG could significantly inhibit the increased expression of both the glycolytic and fibrotic proteins in the activated CF.Conclusion: Cardiac fibrosis is along with the enhancement of CF activation and glycolysis. Glycolysis inhibition can alleviate cardiac fibroblast activation and cardiac fibrosis after myocardial infarction.

scholarly journals The Functional Role of Zinc Finger E Box-Binding Homeobox 2 (Zeb2) in Promoting Cardiac Fibroblast Activation

2018 ◽  
Vol 19 (10) ◽  
pp. 3207 ◽  
Author(s):  
Fahmida Jahan ◽  
Natalie Landry ◽  
Sunil Rattan ◽  
Ian Dixon ◽  
Jeffrey Wigle
Keyword(s):  
Smooth Muscle ◽  
Zinc Finger ◽  
Cardiac Fibrosis ◽  
Smooth Muscle Actin ◽  
Critical Role ◽  
Cardiac Fibroblast ◽  
In Vivo Studies ◽  
Fibroblast Activation ◽  
E Box

Following cardiac injury, fibroblasts are activated and are termed as myofibroblasts, and these cells are key players in extracellular matrix (ECM) remodeling and fibrosis, itself a primary contributor to heart failure. Nutraceuticals have been shown to blunt cardiac fibrosis in both in-vitro and in-vivo studies. However, nutraceuticals have had conflicting results in clinical trials, and there are no effective therapies currently available to specifically target cardiac fibrosis. We have previously shown that expression of the zinc finger E box-binding homeobox 2 (Zeb2) transcription factor increases as fibroblasts are activated. We now show that Zeb2 plays a critical role in fibroblast activation. Zeb2 overexpression in primary rat cardiac fibroblasts is associated with significantly increased expression of embryonic smooth muscle myosin heavy chain (SMemb), ED-A fibronectin and α-smooth muscle actin (α-SMA). We found that Zeb2 was highly expressed in activated myofibroblast nuclei but not in the nuclei of inactive fibroblasts. Moreover, ectopic Zeb2 expression in myofibroblasts resulted in a significantly less migratory phenotype with elevated contractility, which are characteristics of mature myofibroblasts. Knockdown of Zeb2 with siRNA in primary myofibroblasts did not alter the expression of myofibroblast markers, which may indicate that Zeb2 is functionally redundant with other profibrotic transcription factors. These findings add to our understanding of the contribution of Zeb2 to the mechanisms controlling cardiac fibroblast activation.

scholarly journals Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Qiankun Bao ◽  
Bangying Zhang ◽  
Ya Suo ◽  
Chen Liu ◽  
Qian Yang ◽  
...  
Keyword(s):  
Intermittent Hypoxia ◽  
Cardiac Fibrosis ◽  
Synergistic Effects ◽  
Cardiac Fibroblasts ◽  
Cardiac Fibroblast ◽  
Ang Ii ◽  
Fibroblast Activation ◽  
Obstructive Sleep

Intermittent hypoxia (IH) is the predominant pathophysiological disturbance in obstructive sleep apnea (OSA), known to be independently associated with cardiovascular diseases. However, the effect of IH on cardiac fibrosis and molecular events involved in this process are unclear. Here, we tested IH in angiotensin II (Ang II)-induced cardiac fibrosis and signaling linked to fibroblast activation. IH triggered cardiac fibrosis and aggravated Ang II-induced cardiac dysfunction in mice. Plasma thrombospondin-1 (TSP1) content was upregulated in both IH-exposed mice and OSA patients. Moreover, both in vivo and in vitro results showed IH-induced cardiac fibroblast activation and increased TSP1 expression in cardiac fibroblasts. Mechanistically, phosphorylation of STAT3 at Tyr705 mediated the IH-induced TSP1 expression and fibroblast activation. Finally, STAT3 inhibitor S3I-201 or AAV9 carrying a periostin promoter driving the expression of shRNA targeting Stat3 significantly attenuated the synergistic effects of IH and Ang II on cardiac fibrosis in mice. This work suggests a potential therapeutic strategy for OSA-related fibrotic heart disease.

scholarly journals The association between RGS4 and choline in cardiac fibrosis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jing Guo ◽  
Pengzhou Hang ◽  
Jie Yu ◽  
Wen Li ◽  
Xiuye Zhao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Western Blot ◽  
G Protein ◽  
Protein Level ◽  
Cardiac Fibrosis ◽  
Collagen I ◽  
Qrt Pcr ◽  
Tgf Β1

Abstract Background Myocardial fibrosis is caused by the adverse and powerful remodeling of the heart secondary to the death of cardiomyocytes after myocardial infarction. Regulators of G protein Signaling (RGS) 4 is involved in cardiac diseases through regulating G protein-coupled receptors (GPCRs). Methods Cardiac fibrosis models were established through cardiac fibroblasts (CFs) treatment with transforming growth factor (TGF)-β1 in vitro and mice subjected to myocardial infarction in vivo. The mRNA expression of RGS4, collagen I/III and α-SMA detected by qRT-PCR. Protein level of RGS4, collagen I, CTGF and α-SMA detected by Western blot. The ejection fraction (EF%) and fractional shortening (FS%) of mice were measured by echocardiography. Collagen deposition of mice was tested by Masson staining. Results The expression of RGS4 increased in CFs treatment with TGF-β1 and in MI mice. The model of cardiac fibrosis detected by qRT-PCR and Western blot. It was demonstrated that inhibition of RGS4 expression improved cardiac fibrosis by transfection with small interfering RNA in CFs and injection with lentivirus shRNA in mice. The protective effect of choline against cardiac fibrosis was counteracted by overexpression of RGS4 in vitro and in vivo. Moreover, choline inhibited the protein level of TGF-β1, p-Smad2/3, p-p38 and p-ERK1/2 in CFs treated with TGF-β1, which were restored by RGS4 overexpression. Conclusion This study demonstrated that RGS4 promoted cardiac fibrosis and attenuated the anti-cardiac fibrosis of choline. RGS4 may weaken anti-cardiac fibrosis of choline through TGF-β1/Smad and MAPK signaling pathways.

P850Clinical difference of recent myocardial infarction compared with acute myocardial infarction - Insights from Tokyo CCU network multicenter registry

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
R Ito ◽  
M Takayama ◽  
J Yamashita ◽  
K Yahagi ◽  
T Shinke ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Cardiogenic Shock ◽  
Cause Of Death ◽  
Rank Test ◽  
Mechanical Complication ◽  
Recent Myocardial Infarction ◽  
Log Rank Test ◽  
Kaplan Meier ◽  
Multicenter Registry

Abstract Background Although the patient's characteristics and outcome of acute myocardial infarction (AMI) have been sufficiently investigated and primary percutaneous coronary intervention (PCI) has been recognized as established treatment strategy, those of recent myocardial infarction (RMI) have not been fully evaluated. Purpose The purpose of the present study was to clarify clinical characteristics and in-hospital outcomes of RMI patients from the database of the Tokyo CCU network multicenter registry. Methods In Tokyo CCU network multicenter registry database from 2013 to 2016, 15788 consecutive patients were registered as AMI (within 24 hours from onset) and RMI (within 2–30 days from onset). However 1246 patients were excluded because of inadequate data. And we excluded 66 cases because of out of onset period and 129 cases that strongly suspected of involvement of vasospastic events. Therefore, remaining 14347 patients were categorized to RMI group (n=1853) and AMI group (n=12494), and analyzed. Results Compared with AMI group, average age was older (70.4±12.9 vs 68.0±13.4 years, p<0.001), male was less (72.4 vs 76.4%, p<0.001), chest pain as chief complaint was less (75.2 vs 83.6%, p<0.001), prevalence of diabetes mellitus was higher (35.9 vs 31.0%, p<0.001), multi-vessel coronary disease was more (54.7 vs 44.6%, p<0.001), patients undergoing PCI was less (79.0 vs 91.2%, p<0.001), and the incidence of mechanical complication was more in RMI group (3.0 vs 1.5%, p<0.001). Although 30-day mortality was equivalent between 2 groups (5.3 vs 5.8%, p=0.360), the major cause of death in AMI group was cardiogenic shock, while in the RMI group it was a mechanical complication. On Kaplan-Meier analysis, the 2 groups had significantly different cumulative incidence of death due to cardiogenic shock (p=0.006, Log-rank test) and mechanical complication (p=0.021, Log-rank test). Furthermore death due to mechanical complication in AMI group was plateau after about 1 week from hospitalization, whereas in RMI group it continued to increase. Kaplan-Meier analysis Conclusions RMI patients had distinctive clinical features in backgrounds and treatment strategies compared with AMI patients, and the major cause of death of RMI patients was different from that of AMI patients. Furthermore, even though treatment during hospitalization of RMI patients was well done, death due to mechanical complications continued to increase.

scholarly journals The Disruption of the β-Catenin/TCF-1/STAT3 Signaling Axis by 4-Acetylantroquinonol B Inhibits the Tumorigenesis and Cancer Stem-Cell-Like Properties of Glioblastoma Cells, In Vitro and In Vivo

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 491 ◽  
Author(s):  
Heng-Wei Liu ◽  
Yu-Kai Su ◽  
Oluwaseun Bamodu ◽  
Dueng-Yuan Hueng ◽  
Wei-Hwa Lee ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Migration And Invasion ◽  
Rank Test ◽  
Lower Grade ◽  
Aberrant Expression ◽  
Stat3 Signaling ◽  
Log Rank Test ◽  
Signaling Axis

Background: Glioblastoma (GBM), a malignant form of glioma, is characterized by resistance to therapy and poor prognosis. Accumulating evidence shows that the initiation, propagation, and recurrence of GBM is attributable to the presence of GBM stem cells (GBM-CSCs). Experimental approach: Herein, we investigated the effect of 4-Acetylantroquinonol B (4-AAQB), a bioactive isolate of Antrodia cinnamomea, on GBM cell viability, oncogenic, and CSCs-like activities. Results: We observed that aberrant expression of catenin is characteristic of GBM, compared to other glioma types (p = 0.0001, log-rank test = 475.2), and correlates with poor prognosis of GBM patients. Lower grade glioma and glioblastoma patients (n = 1152) with low catenin expression had 25% and 21.5% better overall survival than those with high catenin expression at the 5 and 10-year time-points, respectively (p = 3.57e-11, log-rank test = 43.8). Immunohistochemistry demonstrated that compared with adjacent non-tumor brain tissue, primary and recurrent GBM exhibited enhanced catenin expression (~10-fold, p < 0.001). Western blot analysis showed that 4-AAQB significantly downregulated β-catenin and dysregulated the catenin/LEF1/Stat3 signaling axis in U87MG and DBTRG-05MG cells, dose-dependently. 4-AAQB–induced downregulation of catenin positively correlated with reduced Sox2 and Oct4 nuclear expression in the cells. Furthermore, 4-AAQB markedly reduced the viability of U87MG and DBTRG-05MG cells with 48 h IC50 of 9.2 M and 12.5 M, respectively, effectively inhibited the nuclear catenin, limited the migration and invasion of GBM cells, with concurrent downregulation of catenin, vimentin, and slug; similarly, colony and tumorsphere formation was significantly attenuated with reduced expression of c-Myc and KLF4 proteins. Conclusions: Summarily, we show for the first time that 4-AAQB suppresses the tumor-promoting catenin/LEF1/Stat3 signaling, and inhibited CSCs-induced oncogenic activities in GBM in vitro, with in vivo validation; thus projecting 4-AAQB as a potent therapeutic agent for anti-GBM target therapy.

Abstract 353: Bone Marrow Fibroblast Progenitor Cell-derived Exosomes Activate Resident Fibroblast and Augment Pressure Overload Induced Cardiac Fibrosis in IL10KO Mice

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Suresh K Verma ◽  
Venkata N Girikipathi ◽  
Maria Cimini ◽  
Zhongjian Cheng ◽  
Moshin Khan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cardiac Fibrosis ◽  
Culture Media ◽  
Critical Role ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiac Fibroblast ◽  
Paracrine Factors ◽  
Fibroblast Activation ◽  
Resident Fibroblast

Background: Activated fibroblasts (myoFBs) play critical role in cardiac fibrosis, however, their origin in diseased heart remains uncertain. Previous studies suggest the contribution of bone marrow fibroblasts progenitor cells (FPC) in pressure overload (PO)-induced cardiac fibrosis and inflammation acts as catalyst in this process. Recently others and we have shown that paracrine mediators packaged in exosomes play important role in cardiac pathophysiology. Thus, we hypothesized that exosome-derived from IL10KO-FPC augments PO-induced resident cardiac fibroblast activation and therefore, aggravate cardiac fibrosis. Methods and Results: Cardiac fibrosis was induced in Wild-type (WT) and IL10-knockout (IL10KO) mice by transverse aortic constriction (TAC). TAC-induced left ventricular (LV) dysfunction and fibrosis were further exaggerated in IL10KO mice. PO-enhanced FPC (Prominin1 + cells) mobilization and homing in IL10KO mice compared to WT mice. To establish the IL10KO-FPC paracrine signaling, exosomes were isolated from WT and IL10KO BM-FPC culture media and characterized for proteins/miRNA. IL10 KO FPC-exosomes showed altered packaging of signature fibrotic miR and proteins. To explore whether FPC-exosomes modulate resident fibroblast activation, adult cardiac fibroblasts were treated with WT and IL10KO FPC-derived exosomes. IL10KO-FPC-derived exosomes exaggerate TGFβ 2 -induced activation of adult fibroblasts. These data suggest that fibrotic remodeling factors (miRs and/or proteins) packaged in IL10KO-FPC exosomes are sufficient to enhance the resident cardiac fibroblast activation and mediate cardiac fibrotic remodeling IL10 treatment significantly inhibits TGFβ 2 -induced FPC to myoFBs transition. Conclusion: Taken together, our findings suggest that paracrine factors secreted by BM-FPC augment resident cardiac fibroblast activation and fibrosis in pressure overloaded myocardium and IL10 negatively regulates this process. Ongoing investigations using molecular approaches will provide a better understanding on the mechanistic and therapeutic aspects of IL10 on PO-induced cardiac fibrosis and heart failure.

Abstract 866: Secreted Frizzled Related Protein 2 Modulates Post Myocardial Infarct Remodeling by Inhibiting Collagen Maturation through the Inhibition of Bone Morphogenetic Protein 1 Activity

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Wei He ◽  
Lunan Zhang ◽  
Richard E Pratt ◽  
Victor J Dzau
Keyword(s):  
Myocardial Infarction ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Myocardial Infarct ◽  
Primary Cultures ◽  
The United States ◽  
Coronary Artery Ligation ◽  
Related Protein ◽  
Artery Ligation

Myocardial infarction and post-infarction remodeling with heart failure are the major cause of mortality and morbidity in the United States. We recently reported that intracardiac implantation of genetically engineered mesenchymal stem cell (MSC) overexpressing the Akt gene dramatically reduced the infarct size and restored cardiac functions in rodent hearts after coronary artery ligation. Further, we identified Secreted Frizzled Related Protein 2 (sfrp2) as a key factor released by Akt-MSC mediating myocardial survival and repair. However, the underlying mechanism remains elusive. Bone Morphogenetic Protein1 (BMP1)/Tolloid (TLD)-like metalloproteinases belong to a subgroup of astacin family and play key roles in the regulation of extracelluar matrix (ECM) formation and cardiac fibrosis. These proteases have procollagen C-proteinase (PCP) activities which are responsible for the cleavage of C-propeptides from procollagen precursors to produce mature collagen fibrils. In this report, we showed that three days following myocardial infarction in rats, both BMP1 protein expression and activity were upregulated in the infarcted left ventricle. Interestingly, we found recombinant sfrp2 could inhibit BMP1 activity in MI tissue samples as measured by an in vitro PCP activity assay. Furthermore, using purified recombinant proteins, we demonstrated that sfrp2, but not sfrp1 or sfrp3, inhibited BMP-1 activity in vitro. Moreover, purified sfrp2 could physically interact with BMP1 protein as shown by the co-immunoprecipitation assay. To provide further evidence that sfrp2 can interfere with collagen processing, we demonstrated that exogenously added sfrp2 interfered with procollagen processing in primary cultures of cardiac fibroblast culture medium. Similar results were obtained when these cells were transiently transfected with sfrp2 expressing plasmids. In summary, our data suggest that one of the molecular mechanisms underlying the cardioprotective and repair effects of sfrp2 protein on myocardial infarction is through the inhibition of BMP-1 activity. Therefore, sfrp2 has the potential clinical application as a novel anti-fibrotic reagent for the modulation of cardiac remodeling after acute myocardial infarction.

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