Meox2/Tcf15 异源二聚体为心脏脂肪酸摄取编程心脏毛细血管内皮。
Meox2/Tcf15 heterodimers program the heart capillary endothelium for cardiac fatty acid uptake.
机构信息
From Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology (G.C., I.V., X.L.A., A.L.), Department of Cardiovascular Sciences, Cardiology Unit (S.V., M.S., S.J.), Laboratory of Angiogenesis & Neurovascular link, Vesalius Research Center, VIB/Department of Oncology (S.S., P.C.), and Department of Cardiovascular Sciences, Experimental Cardiac Surgery Unit (P.H.), KULeuven, Belgium; Department of Nuclear Medicine, Clínica Universidad de Navarra/MicroPET Research Unit CIMA-CUN (M.C., I.P.), and Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research (F.P., X.L.A), University of Navarra, Pamplona, Spain; Laboratory of Comparative Neurobiology, Instituto Cavanilles, University of Valencia, CIBERNED, Spain (M.S.S.-P., J.M.G.-V.); and Departments of Abdominal Surgery (B.T.) and Neurosurgery (J.v.L., J.G.), University Hospitals Leuven/KULeuven, Belgium.
出版信息
Circulation. 2015 Mar 3;131(9):815-26. doi: 10.1161/CIRCULATIONAHA.114.013721. Epub 2015 Jan 5.
BACKGROUND
Microvascular endothelium in different organs is specialized to fulfill the particular needs of parenchymal cells. However, specific information about heart capillary endothelial cells (ECs) is lacking.
METHODS AND RESULTS
Using microarray profiling on freshly isolated ECs from heart, brain, and liver, we revealed a genetic signature for microvascular heart ECs and identified Meox2/Tcf15 heterodimers as novel transcriptional determinants. This signature was largely shared with skeletal muscle and adipose tissue endothelium and was enriched in genes encoding fatty acid (FA) transport-related proteins. Using gain- and loss-of-function approaches, we showed that Meox2/Tcf15 mediate FA uptake in heart ECs, in part, by driving endothelial CD36 and lipoprotein lipase expression and facilitate FA transport across heart ECs. Combined Meox2 and Tcf15 haplodeficiency impaired FA uptake in heart ECs and reduced FA transfer to cardiomyocytes. In the long term, this combined haplodeficiency resulted in impaired cardiac contractility.
CONCLUSIONS
Our findings highlight a regulatory role for ECs in FA transfer to the heart parenchyma and unveil 2 of its intrinsic regulators. Our insights could be used to develop new strategies based on endothelial Meox2/Tcf15 targeting to modulate FA transfer to the heart and remedy cardiac dysfunction resulting from altered energy substrate usage.
背景
不同器官的微血管内皮细胞专门满足实质细胞的特殊需求。然而，关于心脏毛细血管内皮细胞（ECs）的具体信息尚不清楚。
方法和结果
我们使用微阵列分析对心脏、大脑和肝脏中分离的 ECs 进行分析，揭示了微血管心脏 ECs 的遗传特征，并鉴定出 Meox2/Tcf15 异二聚体为新的转录决定因子。该特征与骨骼肌和脂肪组织内皮细胞有很大的重叠，并富含编码脂肪酸（FA）转运相关蛋白的基因。通过增益和缺失功能的方法，我们发现 Meox2/Tcf15 通过驱动内皮细胞 CD36 和脂蛋白脂肪酶的表达，介导心脏 ECs 中的 FA 摄取，并促进 FA 在心脏 ECs 中的转运。联合的 Meox2 和 Tcf15 单倍体缺失会损害心脏 ECs 中的 FA 摄取，并减少 FA 向心肌细胞的转移。从长远来看，这种联合的单倍体缺失会导致心脏收缩功能受损。
结论
我们的研究结果强调了内皮细胞在 FA 向心脏实质转移中的调节作用，并揭示了其 2 个内在调节因子。我们的研究结果可以用于开发新的策略，基于内皮细胞 Meox2/Tcf15 的靶向作用来调节 FA 向心脏的转移，并纠正由于能量底物利用改变而导致的心脏功能障碍。
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