Transglutaminase 2 in Arterial Calcification and Atherosclerosis

描述（申请人提供）：动脉平滑肌细胞（SMCs）介导动脉重塑和修复。SMCs具有表型可塑性，可转变为增殖性、迁移性的“合成”SMCs，可调节内膜增生和动脉粥样硬化斑块的稳定性，而SMC软骨-骨性表型转变可促进动脉钙化。我们的中心假设是多功能蛋白转谷氨酰胺酶2 (TG2)，一种已知的伤口修复和组织纤维化的介质，调节动脉粥样硬化病变的钙化和进展。TG2在动脉粥样硬化病变中表达增加。活化的细胞释放TG2， TG2通过转酰胺作用共价交联许多细胞外基质底物蛋白。TG2还具有相互调节TG和GTP结合/GTP酶活性，并且是纤维连接蛋白的整合素共受体。TG2调节SMC的粘附、迁移、分化和功能。慢性血管收缩引起的阻力动脉重构是tg2依赖性的。我们的初步研究表明，TG2调节培养软骨细胞和主动脉SMCs的软骨骨分化和钙化。TG2还调节SMC中钙化抑制剂和促动脉粥样硬化磷酸化蛋白骨桥蛋白的表达，骨桥蛋白是SMC从收缩分化向合成分化转变的标志。在LDL受体敲除的骨髓受体中，骨髓特异性TG2表达限制了动脉粥样硬化病变的大小，TG2似乎驱动了小鼠主动脉瓣钙化。我们将测试相关的假设，即通过修改细胞外基质，细胞外TG2构成性地抑制培养的主动脉SMC从收缩分化向合成分化的转变，但过量的TG2驱动体外表型SMC向软骨骨钙化细胞的转变。我们还将通过研究apoE TG2双敲除小鼠来验证TG2在体内限制动脉粥样硬化斑块易感性的同时促进动脉粥样硬化内膜病变钙化的假设。这些研究的完成将描述调节动脉TG2作为抑制动脉钙化或动脉粥样硬化病变进展的治疗方法的潜力。

DESCRIPTION (provided by applicant): Arterial smooth muscle cells (SMCs) mediate arterial remodeling and repair. SMCs are phenotypically plastic and can transition to proliferative, migratory "synthetic" SMCs that modulate intimal hyperplasia and stability of atherosclerotic plaques, and SMC chondro- osseous phenotypic transition promotes artery calcification. Our central hypothesis is that the multifunctional protein transglutaminase 2 (TG2), a known mediator of wound repair and tissue fibrosis, regulates both atherosclerotic lesion calcification and progression. Expression of TG2 is increased in atherosclerotic lesions. Activated cells release TG2, and TG2 covalently crosslinks numerous extracellular matrix substrate proteins via transamidation. TG2 also has reciprocally regulated TG and GTP binding/GTPase activities, and is an integrin co-receptor for fibronectin. TG2 modulates SMC adhesion, migration, differentiation and function. Resistance artery remodeling induced by chronic vasoconstriction is TG2-dependent. Our Preliminary Studies reveal that TG2 regulates chondro-osseous differentiation and calcification in cultured chondrocytes and aortic SMCs. TG2 also regulates SMC expression of the calcification inhibitor and pro-atherogenic phosphoprotein osteopontin, a marker of the transition of SMCs from contractile to synthetic differentiation. Bone marrow-specific TG2 expression limits atherosclerotic lesion size in LDL receptor knockout bone marrow recipients and TG2 appears to drive mouse aortic valve calcification. We will test the linked hypotheses that extracellular TG2, by modifying the extracellular matrix, constitutively restrains cultured aortic SMC transition from contractile to synthetic differentiation but that excess TG2 drives phenotypic SMC transition to chondro-osseous calcifying cells in vitro. We also will test the hypothesis that TG2 limits atherosclerotic plaque vulnerability while concurrently promoting atherosclerotic intimal lesion calcification in vivo, studying apoE TG2 double knockout mice. Completion of these studies will delineate the potential for modulation of arterial TG2 as a therapy to suppress artery calcification or atherosclerotic lesion progression.