Growth differentiation factor 15 impairs aortic contractile and relaxing function through altered caveolar signaling of the endothelium

2013 ◽  
Vol 304 (5) ◽  
pp. H709-H718 ◽  
Author(s):  
Magdalena Mazagova ◽  
Hendrik Buikema ◽  
Sjoerd W. Landheer ◽  
Peter Vavrinec ◽  
Azuwerus van Buiten ◽  
...  
Keyword(s):  
Vascular Function ◽  
Independent Predictor ◽  
No Synthase ◽  
Wild Type ◽  
Growth Differentiation Factor 15 ◽  
Caveolin 1 ◽  
Endothelial No Synthase ◽  
Differentiation Factor ◽  
Contraction And Relaxation ◽  
Dependent Mechanism

Growth differentiation factor 15 (GDF15) is an independent predictor of cardiovascular disease, and increased GDF15 levels have been associated with endothelial dysfunction in selected patients. We therefore investigated whether GDF15 modulates endothelial function in aortas of wild-type (WT) and GDF15 knockout (KO) mice. Vascular contractions to phenylephrine and relaxation to ACh were assessed in aortas obtained from healthy WT and GDF15 KO mice. The effects of GDF15 pretreatment and the involvement of ROS or caveolae were determined. Phenylephrine-induced contractions and ACh-mediated relaxations were similar in WT and GDF15 KO mice. Pretreatment with GDF15 inhibited contraction and relaxation in both groups. Inhibition of contraction by GDF15 was absent in denuded vessels or after blockade of nitric oxide (NO) synthase. Relaxation in WT mice was mediated mainly through NO and an unidentified endothelium-derived hyperpolarizin factor (EDHF), whereas GDF15 KO mice mainly used prostaglandins and EDHF. Pretreatment with GDF15 impaired relaxation in WT mice by decreasing NO; in GDF15 KO mice, this was mediated by decreased action of prostaglandins. Disruption of caveolae resulted in a similar inhibition of vascular responses as GDF15. ROS inhibition did not affect vascular function. In cultured endothelial cells, GDF15 pretreatment caused a dissociation between caveolin-1 and endothelial NO synthase. In conclusion, GDF15 impairs aortic contractile and relaxing function through an endothelium-dependent mechanism involving altered caveolar endothelial NO synthase signaling.

scholarly journals Growth differentiation factor-15 is a predictive biomarker in primary ventricular fibrillation: The RUTI-STEMI-PVF study

2018 ◽  
Vol 9 (4_suppl) ◽  
pp. S161-S168 ◽  
Author(s):  
C Garcia-Garcia ◽  
F Rueda ◽  
J Lupon ◽  
T Oliveras ◽  
C Labata ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ventricular Fibrillation ◽  
Independent Predictor ◽  
Coronary Intervention ◽  
Growth Differentiation Factor 15 ◽  
St Segment Elevation ◽  
Segment Elevation Myocardial Infarction ◽  
Differentiation Factor ◽  
St Segment ◽  
Percutaneous Coronary

Background: Primary ventricular fibrillation is an ominous complication of ST-segment elevation myocardial infarction, and proper biomarkers for risk prediction are lacking. Growth differentiation factor-15 is a marker of inflammation, oxidative stress and hypoxia with well-established prognostic value in ST-segment elevation myocardial infarction patients. We explored the predictive value of growth differentiation factor-15 in a subgroup of ST-segment elevation myocardial infarction patients with primary ventricular fibrillation. Methods: Prospective registry of ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention from February 2011–August 2015. Growth differentiation factor-15 concentrations were measured on admission. Logistic regression and Cox proportional regression analyses were used. Results: A total of 1165 ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention (men 78.5%, age 62.3±13.1 years) and 72 patients with primary ventricular fibrillation (6.2%) were included. Compared to patients without primary ventricular fibrillation, median growth differentiation factor-15 concentration was two-fold higher in ST-segment elevation myocardial infarction patients with primary ventricular fibrillation (2655 vs 1367 pg/ml, p<0.001). At 30 days, mortality was 13.9% and 3.6% in patients with and without primary ventricular fibrillation, respectively ( p<0.001), and median growth differentiation factor-15 concentration in patients with primary ventricular fibrillation was five-fold higher among those who died vs survivors (13,098 vs 2415 pg/ml, p<0.001). In a comprehensive multivariable analysis including age, sex, clinical variables, reperfusion time, left ventricular ejection fraction, N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T, growth differentiation factor-15 remained an independent predictor of 30-day mortality, with odds ratios of 3.92 (95% confidence interval 1.35–11.39) in patients with primary ventricular fibrillation ( p=0.012) and 1.72 (95% confidence interval 1.23–2.40) in patients without primary ventricular fibrillation ( p=0.001). Conclusions: Growth differentiation factor-15 is a robust independent predictor of 30-day mortality in ST-segment elevation myocardial infarction patients with primary ventricular fibrillation.

Abstract 5016: Growth-Differentiation Factor-15 is an Independent Predictor of Cardiovascular Events and Mortality in Patients with Stable Coronary Artery Disease

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Tibor Kempf ◽  
Jan-Malte Sinning ◽  
Anja Quint ◽  
Christoph Bickel ◽  
Christoph Sinning ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Independent Predictor ◽  
Troponin T ◽  
Receiver Operating Curve ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor ◽  
All Cause Mortality ◽  
Artery Disease ◽  
Stable Cad

Circulating levels of the TGF β-related cytokine, growth-differentiation factor-15 (GDF-15), provide independent prognostic information in patients with unstable coronary artery disease (CAD). To explore the prognostic utility of GDF-15 in patients with stable CAD, we analyzed the relation of GDF-15 to mortality and cardiovascular (CV) events in the AtheroGene registry which enrolled consecutive patients with stable angina and at least one stenosis >30% in a larger coronary artery. Patients were followed for a median of 3.6 years. Serum samples for measurement of GDF-15 along with other biomarkers were available from 1352 patients. Two pre-specified cutoff points (1200 and 1800 ng/L) were used to identify different risk groups. 55.9%, 26.4%, and 17.7% of the patients presented with GDF-15 values <1200 ng/L, between 1200 and 1800 ng/L, and >1800 ng/L, respectively. Increasing levels of GDF-15 were related to age (P<0.001), hypertension (P=0.01), diabetes mellitus (P<0.001), low HDL cholesterol (P<0.001), and the extent of CAD (P=0.001). Moreover, significant relations to hsCRP, troponin T, NT-proBNP, and reduced renal function (GFR) were observed (all P<0.001). Increasing levels of GDF-15 were associated with an increased risk of all-cause mortality (P<0.001, log-rank test), CV mortality (P<0.001), and CV events (P<0.001). Receiver operating curve analyses confirmed GDF-15 as a strong marker of 2-year adverse outcomes (area under the curve for all-cause mortality, 0.79; CV mortality, 0.81; CV events, 0.70). By multiple Cox regression analysis, GDF-15 emerged as an independent predictor of all-cause mortality (HR 2.1 per one standard deviation of lnGDF-15 [95% CI 1.6 –2.8], P<0.001), CV mortality (HR 2.2 [95% CI 1.5–3.3], P<0.001), and CV events (HR 1.7 [95% CI 1.3–2.4], P=0.001) after adjustment for baseline characteristics, clinical variables, LDL/HDL ratio, hsCRP, troponin T, NT-proBNP, and GFR. Patients with a GDF-15 level above 1800 ng/L had a highly elevated risk of CV mortality even in the fully adjusted model (HR 5.2 [95% CI 1.6 –16.1], P=0.005). These data identify GDF-15 as a powerful and independent biomarker of mortality and CV events in patients with stable CAD.

scholarly journals Apolipoprotein E Enhances Endothelial-NO Production by Modulating Caveolin 1 Interaction With Endothelial NO Synthase

Hypertension ◽  
2012 ◽  
Vol 60 (4) ◽  
pp. 1040-1046 ◽  
Author(s):  
Lili Yue ◽  
Jing-Tan Bian ◽  
Ivana Grizelj ◽  
Ana Cavka ◽  
Shane A. Phillips ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
No Synthase ◽  
No Production ◽  
Caveolin 1 ◽  
Endothelial No Synthase

scholarly journals Wild-Type p53 Attenuates Cancer Cell Motility by Inducing Growth Differentiation Factor-15 Expression

Endocrinology ◽  
2011 ◽  
Vol 152 (8) ◽  
pp. 2987-2995 ◽  
Author(s):  
Jung-Chien Cheng ◽  
Hsun-Ming Chang ◽  
Peter C. K. Leung
Keyword(s):  
Cell Migration ◽  
Cell Motility ◽  
Cancer Cell ◽  
Cell Movement ◽  
Migration And Invasion ◽  
Wild Type ◽  
Growth Differentiation Factor 15 ◽  
Cancer Cell Motility ◽  
Differentiation Factor ◽  
Wild Type P53

A major function of the p53 tumor suppressor is the regulation of the cell cycle and apoptosis. In addition to its well-documented functions in malignant cancer cells, p53 can also regulate cell migration and invasion, which contribute to metastasis. Growth differentiation factor-15 (GDF-15), a member of the TGF-β superfamily, has been shown to be a downstream target of p53 and is associated with diverse human diseases and cancer progression. In this study, we examined the potential role of GDF-15 in p53-regulated cancer cell motility. We show that overexpression of wild-type p53 in two highly invasive p53-null human cancer cell lines, SKOV3 and PC3, attenuated cell migration and the movement through Matrigel. Using wild-type p53 and DNA-binding-deficient p53 mutants, we found that the transcriptional activity of p53 is required in the induction of GDF-15 expression. Cell movement through uncoated and Matrigel-coated transwell decreased in response to treatment with recombinant GDF-15, whereas the cell proliferation was not affected by GDF-15 treatment. Moreover, the induction of GDF-15 expression and secretion by p53 and the reduction in cell movement through Matrigel were diminished by treatment with GDF-15 small interfering RNA. This study demonstrates a mechanism by which p53 attenuates cancer cell motility through GDF-15 expression. In addition, our results indicate that GDF-15 mediates the functions of p53 by autocrine/paracrine action.

P6603The predictive role of T786C single nucleotide polymorphism in endothelial no-synthase gene in late left ventricular remodeling after ST-segment elevation myocardial infarction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
O Petyunina ◽  
M P Kopytsya ◽  
A E Berezin ◽  
A A Berezin
Keyword(s):  
Myocardial Infarction ◽  
Single Nucleotide Polymorphism ◽  
Cardiac Remodeling ◽  
Independent Predictor ◽  
No Synthase ◽  
Enos Gene ◽  
Ethical Standards ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Endothelial No Synthase

Abstract Introduction Endothelial NO-synthase (eNOS) is constitutive enzyme, which is expressed in mature endothelial cells and promotes direct vascular dilatation. Single nucleotide polymorphism (SNP) of T786C in eNOS gene may influence on adverse cardiac remodeling after ST-elevation myocardial infarction (STEMI). Purpose To investigate possible associations between SNP T786C in eNOS gene and adverse cardiac remodeling after STEMI Methods 177 acute STEMI patients treated with primary and facilitate percutaneous coronary intervention that were admitted to intensive care unit of a Therapy National Institute were enrolled in the study. Anthropometry, cardiovascular risk assay, coronary angiography, echocardiography and biomarkers' measure were performed at baseline. The DNA extraction was performed with a commercial kit using real-time polymerase chain reaction PCR. All procedures performed in the study involving human participants were in accordance with the ethical standards and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards and approved by the local ethics committee (Protocol No. 8, 29.08.2016). Written informed consent was obtained from each patient. Results There were correlations between 786CC polymorphism in eNOs gene and adverse cardiac remodeling (r=0.48; p=0.001), LDL cholesterol (r=0.32; p=0.012), type 2 diabetes mellitus (r=0.30; p=0.042), diastolic BP (r=−0.26; p=0.048), unstable angina prior to STEMI (r=0.25; p=0.047) and total quantity of complicated STEMI (r=0.23; p=0.042). Additionally, there were not significant relations between 786CC polymorphism in eNOs gene and multiple coronary vessel injury, STEMI localization, levels of circulating biomarkers of myocardial injury, and amount of damaged coronary arteries. Using univariate and multivariate regressive logistic analysis we found that 786CC genotype of eNOS was independent predictor for late adverse LV remodeling (β-coefficient = 1.57342; odds ratio = 4.8231; 95% confidence interval = 1.5349–15.1552; p=0.0071). Conclusions The polymorphism 786CC in eNOs gene was found as an independent predictor for late adverse cardiac remodeling after STEMI. Acknowledgement/Funding None

scholarly journals Cell Cycle-Regulated Inactivation of Endothelial NO Synthase through NOSIP-Dependent Targeting to the Cytoskeleton

2005 ◽  
Vol 25 (18) ◽  
pp. 8251-8258 ◽  
Author(s):  
Michael Schleicher ◽  
Fredrik Brundin ◽  
Steffen Gross ◽  
Werner Müller-Esterl ◽  
Stefanie Oess
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Nuclear Localization ◽  
Nuclear Export ◽  
Vascular Function ◽  
No Synthase ◽  
Nuclear Localization Sequence ◽  
No Production ◽  
Endothelial No Synthase ◽  
Importin Α

ABSTRACT Nitric oxide (NO) plays a key role in vascular function, cell proliferation, and apoptosis. Proper subcellular localization of endothelial NO synthase (eNOS) is crucial for its activity; however, the role of eNOS trafficking for NO biosynthesis remains to be defined. Overexpression of NOS-interacting protein (NOSIP) induces translocation of eNOS from the plasma membrane to intracellular compartments, thereby impairing NO production. Here we report that endogenous NOSIP reduces the enzymatic capacity of eNOS, specifically in the G2 phase of the cell cycle by targeting eNOS to the actin cytoskeleton. This regulation is critically dependent on the nucleocytoplasmic shuttling of NOSIP and its cytoplasmic accumulation in the G2 phase. The predominant nuclear localization of NOSIP depends on a bipartite nuclear localization sequence (NLS) mediating interaction with importin α. Mutational destruction of the NLS abolishes nuclear import and interaction with importin α. Nuclear export is insensitive to leptomycin B and hence different from the CRM1-dependent default mechanism. Inhibition of NOSIP expression by RNA interference completely abolishes G2-specific cytoskeletal association and inhibition of eNOS. These findings describe a novel cell cycle-dependent modulation of endogenous NO levels that are critical to the cell cycle-related actions of NO such as apoptosis or cell proliferation.

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