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。SMC是表型可塑性的，可以转化为增殖性、迁移性的“合成”SMC，调节动脉粥样硬化斑块的内膜增生和稳定性，SMC软骨-骨表型转化促进动脉钙化。我们的中心假设是多功能蛋白转谷氨酰胺酶2(TG2)，一个已知的伤口修复和组织纤维化的中介，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的表达增加。激活的细胞释放TG2，TG2通过转酰胺化共价交联多种细胞外基质蛋白。TG2还具有相互调节的TG和GTP结合/GTP酶活性，是纤维连接蛋白的整合素联合受体。TG2调节SMC的黏附、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调节培养的软骨细胞和主动脉SMCs的软骨-骨分化和钙化。TG2还调节SMC的钙化抑制物和促动脉粥样硬化的磷蛋白骨桥蛋白的表达，骨桥蛋白是SMC从收缩向合成分化转变的标志。骨髓特异的TG2表达限制了低密度脂蛋白受体敲除骨髓受者的动脉粥样硬化病变的大小，TG2似乎促进了小鼠主动脉瓣的钙化。我们将验证相关假设，即细胞外TG2通过改变细胞外基质，结构性地抑制培养的主动脉SMC从收缩向合成分化的转变，但过量的TG2在体外推动表型SMC向软骨骨钙化细胞的转变。我们还将通过研究apoE TG2双基因敲除小鼠，验证TG2在体内限制动脉粥样硬化斑块易损性同时促进动脉粥样硬化内膜病变钙化的假设。这些研究的完成将勾勒出调节动脉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.