Growth Differentiation Factor-15 Deficiency Augments Inflammatory Response and Exacerbates Septic Heart and Renal Injury Induced by Lipopolysaccharide

Abulizi, Palida; Loganathan, Neruja; Zhao, Danyang; Mele, Tina; Zhang, Yixin; Zwiep, Terry; Liu, Kexiang; Zheng, Xiufen

doi:10.1038/s41598-017-00902-5

Cited by 78 publications

(64 citation statements)

References 35 publications

(54 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recently, we also demonstrated that Liproxstatin-1 significantly accelerated the recovery of the hPSC-CMs functional properties such as beating frequency after the ETP treatment [41]. Interestingly, it was shown that treatment of the GDF15 knockout animals with lipopolysaccharide augmented the inflammatory response and aggravated septic heart and renal injury [64]. These recent findings support our hypothesis that GDF15 acts as a preventing agonist against DOX-induced heart injury.…”

Section: Is It Possible To Identify Common Factors Playing a Role In supporting

confidence: 82%

Cardiotoxicity and Heart Failure: Lessons from Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Anticancer Drugs

Sachinidis

2020

Cells

View full text Add to dashboard Cite

Human-induced pluripotent stem cells (hiPSCs) are discussed as disease modeling for optimization and adaptation of therapy to each individual. However, the fundamental question is still under debate whether stem-cell-based disease modeling and drug discovery are applicable for recapitulating pathological processes under in vivo conditions. Drug treatment and exposure to different chemicals and environmental factors can initiate diseases due to toxicity effects in humans. It is well documented that drug-induced cardiotoxicity accelerates the development of heart failure (HF). Until now, investigations on the understanding of mechanisms involved in HF by anticancer drugs are hindered by limitations of the available cellular models which are relevant for human physiology and by the fact that the clinical manifestation of HF often occurs several years after its initiation. Recently, we identified similar genomic biomarkers as observed by HF after short treatment of hiPSCs-derived cardiomyocytes (hiPSC-CMs) with different antitumor drugs such as anthracyclines and etoposide (ETP). Moreover, we identified common cardiotoxic biological processes and signal transduction pathways which are discussed as being crucial for the survival and function of cardiomyocytes and, therefore, for the development of HF. In the present review, I discuss the applicability of the in vitro cardiotoxicity test systems as modeling for discovering preventive mechanisms/targets against cardiotoxicity and, therefore, for novel HF therapeutic concepts.

show abstract

Section: Is It Possible To Identify Common Factors Playing a Role In supporting

confidence: 82%

Cardiotoxicity and Heart Failure: Lessons from Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Anticancer Drugs

Sachinidis

2020

Cells

View full text Add to dashboard Cite

show abstract

“…Zimmers et al [6] demonstrated induction of GDF-15 expression after kidney or lung injury in murine models and suggested that GDF-15 is an early mediator in organ injury. Abulizi et al [28] have determined that GDF-15 deficiency in a lipopolysaccharide-induced renal injury model aggravates renal damage. Other investigators demonstrated that genetic deletion of GDF-15 exacerbated injury in the renal interstitium and tubules in diabetic mice [29].…”

Section: Discussionmentioning

confidence: 99%

Association between Plasma Levels of Growth Differentiation Factor-15 and Renal Function in the Elderly: Korean Frailty and Aging Cohort Study

Kim

Won

et al. 2019

Kidney Blood Press Res

View full text Add to dashboard Cite

Background/Aims: Growth differentiation factor-15 (GDF-15) expression has been reported to increase in response to tissue damage and has recently emerged as a useful biomarker for various diseases. Although emerging evidence supports the clinicopathological value of GDF-15 in renal impairment, few studies have analyzed it in the elderly. Thus, we conducted a cross-sectional study to investigate the association of plasma GDF-15 with renal function and the presence of chronic kidney disease (CKD) in community-dwelling elderly. Materials: The present study was based on the baseline data of the Korean Frailty and Aging Cohort Study (KFACS), a nationwide cohort study that began in 2016. Of the 1,559 participants assessed in the first year, 443 with available plasma GDF-15 data were enrolled in this study. We investigated the association of plasma GDF-15 levels with clinical and biochemical parameters. The study population was divided into two groups according to renal function (CKD and non-CKD groups) to investigate whether GDF-15 can determine the presence of renal dysfunction in the elderly. Plasma GDF-15 was measured by enzyme-linked immunosorbent assay (ELISA) kit. Results: In a simple regression analysis, the levels of plasma GDF-15 were negatively correlated with estimated glomerular filtration rate (eGFR; r = –0.383, p < 0.001). In multiple linear regression analysis, GDF-15 levels were still significantly correlated with eGFR, even after adjusting for other parameters (r = –0.259, p < 0.001). Plasma GDF-15 levels were significantly higher in the elderly with CKD than in those without CKD (2,364.025 ± 1,052.23 ng/L and 1,451.23 ± 835.79 ng/L, respectively; p < 0.001). The optimal cut-off value of plasma GDF-15 for detecting the presence of CKD was 1,699.4 ng/L (76.5% sensitivity and 76.0% specificity), as determined by the receiver operating characteristic curve. The area under the curve was 0.793 ± 0.033 (95% CI 0.729–0.857, p < 0.001). Conclusion: Plasma GDF-15 levels were negatively associated with eGFR and were significantly increased in the elderly with CKD. Our results suggested that plasma GDF-15 might be a useful marker for discriminating renal impairment in the elderly. Further large and prospective outcome studies of extended duration are needed.

show abstract

“…Myocardial dysfunction is a fatal complication of patients with sepsis [18]. Researches have found that 50% of patients with sepsis have systolic and diastolic dysfunction in left and right ventricular, possibly caused by endotoxin-induced myocardial injury [36] which has been confirmed both in animal and clinical observations [37]. In this study, we also confirm that CLP-induced sepsis caused serious myocardial damage characterized by significant reduction of left ventricular systolic and diastolic functions in mice, which closely mimicked the pathological features of myocardial infarction observed in clinical patients [38].…”

Section: Discussionmentioning

confidence: 86%

Therapeutic efficacy of Schistosoma japonicum cystatin on sepsis-induced cardiomyopathy in a mouse model

Gao

Xie

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Myocardial dysfunction is one of the most common complications of multiple organ failure in septic shock and significantly increases mortality in patients with sepsis. In spite of many studies have confirmed that helminth-derived proteins have strong immunomodulatory functions and could be used to treat inflammatory diseases, there is no report on the therapeutic effect of Schistosoma japonicum -produced cystatin ( Sj- Cys) on the sepsis-induced cardiac dysfunction. Methods A model of sepsis-induced myocardial injury was established by cecal ligation and puncture (CLP) in mouse. Upon CLP operation, each mouse was intraperitoneally treated with 10 µg of recombinant Sj -Cys (r Sj -Cys). Twelve hours after CLP operation, the systolic and diastolic functions of left ventricular were examined by echocardiography. The levels of myoglobin (Mb), cardiac troponin I (cTnI), N-terminal pro-Brain Natriuretic peptide (NT-proBNP) in sera and the activity of myeloperoxidase (MPO) in cardiac tissues were examined as biomarkers for heart injury. The heart tissue was collected for checking pathological changes, macrophages and pro-inflammatory cytokine levels. To address the signaling pathway involved in the anti-inflammatory effects of r Sj -Cys, myeloid differentiation factor 88 (MyD88) was determined by Western blot in heart tissue of mice with sepsis and LPS-stimulated H9C2 cardiomyocyte cells. In addition, the therapeutic effects of r Sj -Cys on LPS-induced cardiomyocyte apoptosis were also detected in H9C2 cells.The levels of M1 biomarker iNOS and M2 biomarker Arg-1 were detected in heart tissue. The pro-inflammatory cytokines TNF-α and IL-6 and regulatory cytokines IL-10 and TGF-β were measured in sera and their mRNA levels in heart tissue of r Sj -Cys-treated mice. Results After being treated with r Sj -Cys, the sepsis-induced heart malfunction was largely improved. The inflammation and injury of heart tissue were also significantly alleviated characterized as significantly decreased infiltration of inflammatory cells in cardiac tissues and fiber swelling, reduced levels of Mb, cTnI and NT-proBNP in sera and MPO activity in heart tissue. The therapeutic efficacy of r Sj -Cys is associated with down-regulated pro-inflammatory cytokines (TNF-α, IL-6) , as well as the decreased M1 macrophages and increased M2 macrophages, possibly through inhibiting LPS-MyD88 signal pathway. Conclusions Recombinant Sj -Cys significantly reduced sepsis-induced cardiomyopathy and could be considered as be a potential therapeutic agent for the prevention and treatment of sepsis associated cardiac dysfunction.

show abstract

Growth Differentiation Factor-15 Deficiency Augments Inflammatory Response and Exacerbates Septic Heart and Renal Injury Induced by Lipopolysaccharide

Cited by 78 publications

References 35 publications

Cardiotoxicity and Heart Failure: Lessons from Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Anticancer Drugs

Cardiotoxicity and Heart Failure: Lessons from Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Anticancer Drugs

Association between Plasma Levels of Growth Differentiation Factor-15 and Renal Function in the Elderly: Korean Frailty and Aging Cohort Study

Therapeutic efficacy of Schistosoma japonicum cystatin on sepsis-induced cardiomyopathy in a mouse model

Contact Info

Product

Resources

About