| BackgroundGDF-15 is a distant member of the transforming growth factor-βcytokine superfamily. Like other TGF-β-related cytokines, GDF-15 is synthesized as a precursor protein that undergoes disulfide-linked dimerization. Proteolysis cleaves the correctly folded GDF-15 precursor protein into the N-terminal pro-peptide and the mature GDF-15 peptide, which is then secreted as a disulfide-linked dimer with an Mr of -28,000. Physiologically, GDF-15 is weakly produced in most tissues, including the heart. In response to pathological or environmental stress, however, GDF-15 production may sharply increase. For example,GDF-15 is upregulated in hepatocytes following toxic liver injury or in cortical neurons following cryoinjury . It appears therefore that GDF-15 is part of a generic gene program that is activated in response to external stressors. However, expression of GDF15 is induced rapidly by IL-1, TNFα, and TGF-βin macrophages, thereby limiting macrophage activation and inflammation (Figure 1).9 In addition, p53, a tumor suppressor protein, induces expression of GDF15, which acts as a growth inhibitory molecule in tumor cells (Figure 1).10 Such growth inhibitory actions of GDF15 are unique compared with those of other targets of p53, such as p21/Waf-1, because GDF15 can act on neighboring cells as an "extracellular" messenger after being secreted.Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor cytokine superfamily and is induced in the myocardium after ischemia and reperfusion injury, and is an independent risk indicator for adverse cardiovascular events. We have identified GDF-15 by cDNA expression array analysis as a gene that is strongly upregulated by nitrosative stress in cultured cardiomyocytes isolated from 1- to 3-day-old rats. GDF-15 mRNA and pro-peptide expression levels were also induced in cardiomyocytes subjected to simulated ischemia/reperfusion (I/R) via NO-peroxynitrite-dependent signaling pathways. GDF-15 was actively secreted into the culture supernatant, suggesting that it might exert autocrine/paracrine effects during I/R. To explore the in vivo relevance of these findings, mice were subjected to transient or permanent coronary artery ligation. Myocardial GDF-15 mRNA and pro-peptide abundance rapidly increased in the area-at-risk after ischemic injury. To delineate the function of GDF-15 during I/R, Gdf-15 gene-targeted mice were subjected to transient coronary artery ligation for 1 hour followed by reperfusion for 24 hours. Gdf-15-deficient mice developed greater infarct sizes and displayed more cardiomyocyte apoptosis in the infarct border zone after I/R compared with wild-type littermates, indicating that endogenous GDF-15 limits myocardial tissue damage in vivo. Moreover, treatment with recombinant GDF-15 protected cultured cardiomyocytes from apoptosis during simulated I/R.Coronary reperfusion is the primary therapeutic goal in patients with acute myocardial infarction (AMI). Although reperfusion is essential for myocardial salvage, it may at first exacerbate cellular damage sustained during the ischemic period, a phenomenon known as reperfusion injury. There is growing evidence that the myocardium adapts to ischemia/reperfusion (I/R) by synthesizing and responding to a variety of stress-induced growth factors and cytokines, and that identification of these endogenous homeostatic mechanisms may open new avenues to limit I/R injury.At present, there is no related literature refer to serum levels of growth-differentiation factor-15 (GDF-15) in the cardiovascular diseases. The study based on the research result abroad, to determine the serum levels of GDF-15 at STEMI, NSTEMI, CAD and health control by ELISA assay. To explore the possibility as the new biomarker of CAD or AMI, and analyze the relationship between GDF-15 and the character of coronary artery. Further, randomize to choose a subset of subjects to research the change of GDF-15 after the medical care for a week.Objectives1. To determine the serum levels of GDF-15 at STEMI, NSTEMI, CAD and health control by ELISA assay2. To explore the possibility as the new biomarker of CAD or AMI3. To analyze the relationship between GDF-15 and the character of coronary artery4. To research the change of serum levels of GDF-15 after the medical care for a week5. To compare GDF-15 with other clinical biomarkersMethods1. By informed consent form, the study will collect subjects including STEMI, NSTEMI, CAD and health control from the department of emergency room , cardiology and CCU of Beijing union hospital since 2007-8 and complete the collection of clinical data, CAG, ECG, cTnI, and so on 2. At the level of protein, to determine the serum levels of GDF-15 at STEMI, NSTEMI, CAD and health control by ELISA assay3. By the statistical software SPSS13.0, accomplish the statistics and to compare the difference between groups.Results1. By logistic regression, the STEMI, NSTEMI patients displayed significantly (P<0.01) higher GDF-15 levels as compared with the healthy controls . The serum levels of GDF-15 is negative correlation with the groups (p<0.001,r=-0.371) , GDF-15 is highest in STEMI and lowest in health control.2. The patients of multi-vascular disease displayed significantly (P<0.01) higher GDF-15 levels as compared with the single vascular group. And the coronary artery severe group is significantly (P<0.01) higher GDF-15 levels as compared with the mild group.3. The ACS patients displayed significantly (P<0.001) higher GDF-15 levels as compared with the health controls. And GDF-15 levels is positive correlation with the health control (p<0.001, r=0.45) .4. The ACS patients displayed significantly (P<0.001) higher GDF-15 levels as compared with the CAD group. And GDF-15 levels is positive correlation with the health control (p<0.001, r=0.309) .5. By the ROC curve diagnosis system, GDF-15 can be the new biomarker of ACS, and have the significant deviation (P<0.001). the higher of the GDF-15,the more possibility of the diagnosis of ACS. It's diagnosis character better than CR, but weaker than BNP,hsCRP.6. Under the three level of GDF-15 in the ACS group, the number of coronary artery diseases displayed significant deviation(p<0.01). And the higher of the GDF-15 level, the more arteries of the coronary artery disease.7. Under the three level of GDF-15 in the ACS group, the degree of the coronary artery diseases displayed significant deviation(p<0.05). And the higher of the GDF-15 level, the heavier of the coronary artery disease.8. The serum levels of GDF-15 after the medical care for a week displayed significant deviation(P<0.01), and is the significant positive correlation between the two groups(p<0.001,r=0.676).Conclusions 1. The STEMI, NSTEMI patients displayed significantly (P<0.001) higher GDF-15 levels as compared with the healthy controls .And the higher of the GDF-15 level, the heavier of the coronary artery disease.2. The ACS patients displayed significantly (P<0.001) higher GDF-15 levels as compared with the health controls. And GDF-15 levels is positive correlation with the health control (p<0.001, r=0.45) .3. The ACS patients displayed significantly (P<0.001) higher GDF-15 levels as compared with the CAD group. And GDF-15 levels is positive correlation with the health control (p<0.001, r=0.309) .4. GDF-15 can be the new biomarker of ACS, and have the significant deviation (P<0.001). the higher of the GDF-15,the more possibility of the diagnosis of ACS. It's better than CR, but weaker than BNP,hsCRP.5. Under the three level of GDF-15 in ACS group , the number of coronary artery diseases displayed significant deviation(p<0.01). And the higher of the GDF-15 level, the more arteries of the coronary artery disease.6. Under the three level of GDF-15 in ACS group , the degree of the coronary artery diseases displayed significant deviation(p<0.05). And the higher of the GDF-15 level, the heavier of the coronary artery disease.7. The serum levels of GDF-15 can be a new biomarker of the efficacy of ACS treatment. |
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