Transglutaminase 2 in Arterial Calcification and Atherosclerosis

转谷氨酰胺酶 2 在动脉钙化和动脉粥样硬化中的作用

• 批准号: 7388360
• 负责人: Robert A. Terkeltaub
• 金额: $ 34.63万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388360
• 关键词: Affect; Aging; Apolipoprotein E; Arterial Fatty Streak; Arterial Injury; Arteries; Atherosclerosis; Attenuated; Automobile Driving; Basement membrane; Bone Marrow; Calcified; Catalytic Domain; Cell Adhesion; Cell Communication; Cell Differentiation process; Cell Proliferation; Cells; Chondrocytes; Chronic; Collagen; Collagen Type I; Condition; Crossbreeding; Diabetes Mellitus; Diet; Elastin; Extracellular Matrix; Fatty acid glycerol esters; Fibronectin Receptors; Fibronectins; Fibrosis; GTP Binding; Glycoproteins; Guanosine Triphosphate Phosphohydrolases; Hyperplasia; In Vitro; Inflammation; Inflammatory; Injury; Integrins; Knock-out; Knockout Mice; Laminin; Laminin Receptor; Lesion; Link; Low Density Lipoprotein Receptor; Maintenance; Mediating; Mediator of activation protein; Membrane Proteins; Metaplasia; Modeling; Mus; Nodule; Pathologic; Phenotype; Phosphoproteins; Physiological; Plastics; Proliferating; Proteins; Proteolysis; Publishing; Recombinants; Resistance; Rest; Rupture; Signal Transduction; Site; Smooth Muscle Myocytes; Tenascin; Testing; Text; Tissues; Transfection; Uremia; Week; Wound Healing; aortic valve; arterial remodeling; bone; calcification; calcification inhibitor; chondro osseous differentiation; congenic; crosslink; extracellular; feeding; in vivo; injured; low density lipoprotein inhibitor; mRNA Expression; macrophage; matrix Gla protein; migration; mutant; osteopontin; prevent; receptor; repaired; response; response to injury; restenosis; restraint; size; surface coating; transglutaminase 2; vasoconstriction

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.

描述（由申请方提供）：动脉平滑肌细胞（SMC）介导动脉重塑和修复。SMC在表型上是可塑的，并且可以转变为增殖的、迁移的“合成”SMC，其调节内膜增生和动脉粥样硬化斑块的稳定性，并且SMC软骨-骨表型转变促进动脉钙化。我们的中心假设是多功能蛋白质转氨酶2（TG 2），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钙化和进展。TG 2的表达在动脉粥样硬化病变中增加。活化的细胞释放TG 2，并且TG 2通过转酰胺作用共价交联许多细胞外基质底物蛋白。TG 2还具有β调节的TG和GTP结合/GTP酶活性，并且是纤连蛋白的整合素共受体。TG 2调节SMC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TG 2依赖性的。我们的初步研究表明，TG 2调节培养的软骨细胞和主动脉平滑肌细胞的软骨-骨分化和钙化。TG 2还调节SMC的钙化抑制剂和促动脉粥样硬化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物。骨髓特异性TG 2表达限制LDL受体敲除骨髓受体的动脉粥样硬化病变大小，TG 2似乎驱动小鼠主动脉瓣钙化。我们将测试相关的假设，即细胞外TG 2，通过修改细胞外基质，组成性抑制培养的主动脉SMC从收缩到合成分化的转变，但过量的TG 2驱动表型SMC在体外向软骨-骨钙化细胞的转变。我们还将测试TG 2限制动脉粥样硬化斑块的脆弱性，同时促进动脉粥样硬化内膜病变钙化在体内的假设，研究apoE TG 2双敲除小鼠。这些研究的完成将描述动脉TG 2调节作为抑制动脉钙化或动脉粥样硬化病变进展的治疗的潜力。