腫瘤內皮標記物1(tumor endothelial marker 1, TEM1)，又被稱為CD248，是一個第一型跨膜糖蛋白，主要存在於胚胎發育過程從間質細胞衍生出來的細胞中。TEM1的表現在不少疾病的病理變化中會增加表現，例如癌症轉移、器官纖維化、動脈粥狀硬化和傷口修復。TEM1在心臟中的表現和功能過去從未被研究過。在之前我們的研究中，我們發現在末期心臟衰竭病人的心肌細胞，TEM1的表現會明顯地增加；而不止心肌細胞，心臟纖維母細胞也會表現TEM1。我們假設心臟中TEM1的細胞外結構會被釋放形成可溶性TEM1，並在週邊循環的血液中能被檢測出來。
在本研究中，我們使用人類心臟纖維母細胞(HCF)和大鼠心肌細胞(H9c2細胞)來做培養，並用不同的壓力條件做處理。然後收集各細胞的培養基質，透過西方點墨法和酵素結合免疫吸附分析法(ELISA)，來檢測可溶性TEM1是否存在。我們進行了一個病例對照研究，以比較患有心臟衰竭及心臟功能正常的病患血清中TEM1的濃度。此外，我們追蹤了這些心臟衰竭的病患，以比較在不同臨床狀態下，血清中TEM1濃度的變化；我們也分析了心臟衰竭病患血清中TEM1與各種心臟衰竭生物標記和發炎性生物標記之間的相關性。研究的結果，我們發現可溶性TEM1的確存在於HCF和H9c2細胞的細胞培養基質中，顯示TEM1會從這些受損的心肌細胞和心臟纖維母細胞中釋放出來。而在病例對照研究中，我們發現心臟衰竭病患的血清中TEM1濃度，相較於心臟功能正常的對照組並沒有明顯的差異(0.72 vs 0.72 ng/ml, p=0.996)。在經過年齡、性別和共病症1:1匹配後，我們依然看到了同樣的結果(0.74 vs 0.73 ng/ml, p=0.981)。而在心臟衰竭病例追蹤研究中，於急性失償狀態下血清中腦利鈉(BNP)的濃度是明顯地高於在穩定狀態下的濃度(3360.8 vs 1430.7 pg/ml, p=0.0001)；然而，兩種狀態下所測得的血清可溶性TEM1的濃度並沒有顯著的差異(0.99 vs 1.13 ng/ml, p=0.299)。而我們也發現，這些心臟衰竭病患的血清可溶性TEM1濃度，與兩種心臟衰竭的生物標記有相關性，一是生長分化因子-15 (GDF-15, ρ=0.458, p=0.013) ，而另一為半乳糖凝集素-3 (galectin-3, ρ=0.321, p=0.090)。但沒有發現TEM1與其他發炎性生物標記有相關性。
總結，我們的研究顯示TEM1在受損的心肌細胞和心臟纖維母細胞會顯著增加，並且這種蛋白質會從細胞中釋放到周圍的循環中。心臟衰竭病患血清中可溶性TEM1的濃度，與沒有心臟衰竭的病患相比，並沒有顯著的差異；然而它與其他心臟衰竭的生物標記有相關性。

Tumor endothelial marker 1 (TEM1), also known as CD248, is a type I transmembrane glycoprotein and was mainly found in mesenchymal lineage-derived cells during embryogenesis. TEM1 expression was re-upreagulated in pathological conditions, such as cancer metastasis, organ fibrosis, atherosclerosis and wound repair. The expression and function of TEM1 in the heart have never been investigated before. In the previous study, we found TEM1 expression was upregulated in the myocardium of end-stage heart failure (HF) patients. Both cardiomyocytes and cardiac fibroblasts could express TEM1. We hypothesized that the extracellular domain of TEM1 in heart could be released to form soluble TEM1 (sTEM1) in HF and be detected in the peripheral circulation of HF patients.
In our study, human cardiac fibroblast (HCF) and rat cardiomyocyte cells (H9c2 cells) were cultured and treated with different stress conditions. The culture media were collected and the presence of soluble TEM1 was detected by western blotting and enzyme-linked immunosorbent assay. A case-control study was conducted to compare the serum levels of sTEM1 in patients with and without HF. In the HF cohort, we compared the serum levels of sTEM1 in different clinical statuses of heart failure. We also looked at the correlation between sTEM1 and other HF biomarkers and inflammatory biomarkers. The sTEM1 was detectable in the culture media of H9c2 cells and HCFs indicating that TEM1 did release from the injured cardiac cells. In the case-control study, the serum levels of sTEM1in patients with heart failure were not significantly different from those in the control group (0.72 vs 0.72 ng/ml, p=0.996). The same results were observed after 1:1 frequency matching of age, sex, and comorbidities (0.74 vs 0.73 ng/ml, p=0.981). In the HF cohort, the serum level of brain natriuretic peptide (BNP) was higher in the acute decompensated status and lower in the stable status (3360.8 vs 1430.7 pg/ml, p=0.0001). Nevertheless, there was no significant difference in serum level of sTEM1 between the two different statuses (0.99 vs 1.13 ng/ml, p=0.299). The serum level of sTEM1 had a significant correlation with an HF biomarker, growth differentiation factor-15 (GDF-15, ρ=0.458, p=0.013) and a borderline correlation with galectin-3 (ρ=0.321, p=0.090). But no correlations with inflammatory biomarkers were found.
In conclusion, our study showed that TEM1 was significantly upregulated in injured cardiac cells and this protein was released from the cells into the peripheral circulation. The serum level of sTEM1 in HF patients was not different from those without HF, but its concentration was correlated with other HF biomarkers.

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