From the Division of Cardiovascular Genomics (M.M.S., H.A.T., H.F.A., A.R., C.C., J.S., J.L.M.B.), Division of Vascular Biology, Department of Medical Biochemistry and Biophysics (M.M.S., H.A.T., J.J.H., C.N., H.F.A., A.R., C.C., C.B., J.S., J.L.M.B.), Computational Medicine Unit, Department of Medicine Solna, Center of Molecular Medicine (M.M.S.), and Department of Environmental Medicine (B.G., K.L., U.d.F.), Karolinska Institutet, Solna, Sweden; Clinical Gene Networks AB, Karolinska Science Park, Solna, Sweden (M.M.S., A.R., J.L.M.B.); Division of Cardiovascular Genomics, Department of Pathological Anatomy and Forensic Medicine, University of Tartu, Tartu, Estonia (R.K.J., A.R., J.L.M.B.); Cardiovascular Genetics and Genomics, Department of Medicine Solna, Karolinska Institutet, Solna, Sweden (A.S., A.H.); Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia (A.R.); Department of Clinical Sciences, Hypertension and Cardiovascular Disease, Clinical Research Center, Skåne University Hospital, Malmö, Sweden (O.M.); Department of Cardiothoracic Surgery and Anesthesiology and Department of Molecular Medicine and Surgery, Karolinska University Hospital Solna, Karolinska Institutet, Sweden (T.I.); School of Life Sciences-LifeNet, Freiburg Institute for Advanced Studies, University of Freiburg, Freiburg im Breisgau, Germany (T.M.); The Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, United Kingdom (T.M.); and Institute for Genomics and Multi-Scale Biology, Mount Sinai School of Medicine, New York, NY (E.E.S., J.L.M.B.).
Arterioscler Thromb Vasc Biol. 2014 Sep;34(9):2068-77. doi: 10.1161/ATVBAHA.113.302709. Epub 2014 Jun 12.
Using a multi-tissue, genome-wide gene expression approach, we recently identified a gene module linked to the extent of human atherosclerosis. This atherosclerosis module was enriched with inherited risk for coronary and carotid artery disease (CAD) and overlapped with genes in the transendothelial migration of leukocyte (TEML) pathway. Among the atherosclerosis module genes, the transcription cofactor Lim domain binding 2 (LDB2) was the most connected in a CAD vascular wall regulatory gene network. Here, we used human genomics and atherosclerosis-prone mice to evaluate the possible role of LDB2 in TEML and atherosclerosis.
mRNA profiles generated from blood macrophages in patients with CAD were used to infer transcription factor regulatory gene networks; Ldlr(-/-)Apob(100/100) mice were used to study the effects of Ldb2 deficiency on TEML activity and atherogenesis. LDB2 was the most connected gene in a transcription factor regulatory network inferred from TEML and atherosclerosis module genes in CAD macrophages. In Ldlr(-/-)Apob(100/100) mice, loss of Ldb2 increased atherosclerotic lesion size ≈2-fold and decreased plaque stability. The exacerbated atherosclerosis was caused by increased TEML activity, as demonstrated in air-pouch and retinal vasculature models in vivo, by ex vivo perfusion of primary leukocytes, and by leukocyte migration in vitro. In THP1 cells, migration was increased by overexpression and decreased by small interfering RNA inhibition of LDB2. A functional LDB2 variant (rs10939673) was associated with the risk and extent of CAD across several cohorts.
As a key driver of the TEML pathway in CAD macrophages, LDB2 is a novel candidate to target CAD by inhibiting the overall activity of TEML.
使用多组织全基因组基因表达方法，我们最近确定了一个与人类动脉粥样硬化程度相关的基因模块。这个动脉粥样硬化模块富含与冠状动脉和颈动脉疾病（CAD）相关的遗传风险，并且与白细胞跨内皮迁移（TEML）途径中的基因重叠。在动脉粥样硬化模块基因中，转录共因子 Lim 结构域结合蛋白 2（LDB2）是 CAD 血管壁调节基因网络中连接最紧密的基因。在这里，我们使用人类基因组学和动脉粥样硬化易感小鼠来评估 LDB2 在 TEML 和动脉粥样硬化中的可能作用。
从 CAD 患者的血液巨噬细胞中生成的 mRNA 图谱用于推断转录因子调节基因网络；使用 Ldlr（-/-）Apob（100/100）小鼠研究 Ldb2 缺乏对 TEML 活性和动脉粥样硬化形成的影响。LDB2 是从 CAD 巨噬细胞的 TEML 和动脉粥样硬化模块基因推断出的转录因子调节网络中连接最紧密的基因。在 Ldlr（-/-）Apob（100/100）小鼠中，Ldb2 的缺失增加了动脉粥样硬化病变的大小约 2 倍，并降低了斑块的稳定性。通过体内空气囊和视网膜血管模型、原代白细胞的体外灌注以及体外白细胞迁移，证明了 TEML 活性的增加导致了加剧的动脉粥样硬化。在 THP1 细胞中，过表达 LDB2 会增加迁移，而用小干扰 RNA 抑制 LDB2 则会减少迁移。一个功能性的 LDB2 变体（rs10939673）与几个队列中 CAD 的风险和严重程度相关。
作为 CAD 巨噬细胞中 TEML 途径的关键驱动因素，LDB2 是通过抑制 TEML 的整体活性来靶向 CAD 的一个新的候选基因。
