Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.
Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden.
Cardiovasc Res. 2023 Sep 5;119(11):2061-2073. doi: 10.1093/cvr/cvad079.
Transforming growth factor-beta (TGF-β) exists in three isoforms TGF-β1, -β2, and -β3. TGF-β1 has been suggested to be important for maintaining plaque stability, yet the role of TGF-β2 and -β3 in atherosclerosis remains to be investigated.This study explores the association of the three isoforms of TGF-β with plaque stability in the human atherosclerotic disease.
TGF-β1, -β2, and -β3 proteins were quantified in 223 human carotid plaques by immunoassays. Indications for the endarterectomy were: symptomatic carotid plaque with stenosis >70% or without symptoms and >80% stenosis. Plaque mRNA levels were assessed by RNA sequencing. Plaque components and extracellular matrix were measured histologically and biochemically. Matrix metalloproteinases and monocyte chemoattractant protein-1 (MCP-1) was measured with immunoassays. The effect of TGF-β2 on inflammation and protease activity was investigated in vitro using THP-1 and RAW264.7 macrophages. Patients were followed longitudinally for cardiovascular (CV) events.TGF-β2 was the most abundant isoform and was increased at both protein and mRNA levels in asymptomatic plaques. TGF-β2 was the main determinant separating asymptomatic plaques in an Orthogonal Projections to Latent Structures Discriminant Analysis. TGF-β2 correlated positively to features of plaque stability and inversely to markers of plaque vulnerability. TGF-β2 was the only isoform inversely correlated to the matrix-degrading matrix metalloproteinase-9 and inflammation in the plaque tissue. In vitro, TGF-β2 pre-treatment reduced MCP-1 gene and protein levels as well as matrix metalloproteinase-9 gene levels and activity. Patients with plaques with high TGF-β2 levels had a lower risk to suffer from future CV events.
TGF-β2 is the most abundant TGF-β isoform in human plaques and may maintain plaque stability by decreasing inflammation and matrix degradation.
转化生长因子-β（TGF-β）存在三种亚型 TGF-β1、-β2 和 -β3。TGF-β1 被认为对维持斑块稳定性很重要，但 TGF-β2 和 -β3 在动脉粥样硬化中的作用仍有待研究。本研究探讨了三种 TGF-β 亚型与人类动脉粥样硬化疾病中斑块稳定性的关系。
通过免疫测定法在 223 个人颈动脉斑块中定量测定 TGF-β1、-β2 和 -β3 蛋白。进行颈动脉内膜切除术的指征是：有症状的颈动脉斑块狭窄>70%或无症状但>80%狭窄。通过 RNA 测序评估斑块 mRNA 水平。通过组织学和生化方法测量斑块成分和细胞外基质。通过免疫测定法测量基质金属蛋白酶和单核细胞趋化蛋白-1（MCP-1）。使用 THP-1 和 RAW264.7 巨噬细胞在体外研究 TGF-β2 对炎症和蛋白酶活性的影响。对患者进行心血管（CV）事件的纵向随访。TGF-β2 是最丰富的亚型，在无症状斑块中蛋白和 mRNA 水平均升高。TGF-β2 是正交投影到潜在结构判别分析中区分无症状斑块的主要决定因素。TGF-β2 与斑块稳定性的特征呈正相关，与斑块易损性的标志物呈负相关。TGF-β2 是唯一与斑块组织中基质降解的基质金属蛋白酶-9 和炎症呈负相关的亚型。在体外，TGF-β2 预处理可降低 MCP-1 基因和蛋白水平以及基质金属蛋白酶-9 基因水平和活性。TGF-β2 水平较高的斑块患者发生未来 CV 事件的风险较低。
TGF-β2 是人类斑块中最丰富的 TGF-β 亚型，通过减少炎症和基质降解来维持斑块稳定性。
