Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
FASEB J. 2023 Apr;37(4):e22841. doi: 10.1096/fj.202201899R.
Excess deposition of extracellular matrix in the myocardium is a predictor of reduced left ventricular function. Although reducing the hemodynamic load is known to improve myocardial fibrosis, the mechanisms underlying the reversal of the fibrosis have not been elucidated. We focused on the elasticity of myocardial tissue, which is assumed to influence the fibroblast phenotype. Normal and fibrotic myocardium were cultured in 16 kPa and 64 kPa silicone gel-coated dishes supplemented with recombinant TGFβ protein, respectively. Matrix-degrading myocardium was cultured in 64 kPa silicone gel-coated dishes with recombinant TGFβ protein and then in 16 kPa silicone gel-coated dishes. Cardiac fibroblasts were cultured in this three-part in vitro pathological models and compared. Fibroblasts differentiated into activated or matrix-degrading types in response to the pericellular environment. Comprehensive gene expression analysis of fibroblasts in each in vitro condition showed Selenbp1 to be one of the genes responsible for regulating differentiation of fibroblasts. In vitro knockdown of Selenbp1 enhanced fibroblast activation and inhibited conversion to the matrix-degrading form. In vivo knockdown of Selenbp1 resulted in structural changes in the left ventricle associated with progressive tissue fibrosis and left ventricular diastolic failure. Selenbp1 is involved in regulating fibroblast differentiation and appears to be one of the major molecules regulating collagen turnover in cardiac fibrosis.
心肌细胞外基质的过度沉积是左心室功能降低的预测因子。虽然降低血液动力学负荷已被证明可以改善心肌纤维化，但纤维化逆转的机制尚未阐明。我们专注于心肌组织的弹性，假设它会影响成纤维细胞表型。正常和纤维化的心肌分别在补充重组 TGFβ 蛋白的 16 kPa 和 64 kPa 硅凝胶包被培养皿中培养。在含有重组 TGFβ 蛋白的 64 kPa 硅凝胶包被培养皿中培养基质降解的心肌，然后在 16 kPa 硅凝胶包被培养皿中培养。将心脏成纤维细胞在这三个部分的体外病理模型中培养并进行比较。成纤维细胞根据细胞周围环境分化为激活型或基质降解型。对每种体外条件下成纤维细胞的综合基因表达分析表明，Sel enbp1 是负责调节成纤维细胞分化的基因之一。体外 Sel enbp1 敲低增强了成纤维细胞的激活，并抑制了向基质降解形式的转化。体内 Sel enbp1 敲低导致与进行性组织纤维化和左心室舒张功能衰竭相关的左心室结构改变。Sel enbp1 参与调节成纤维细胞分化，似乎是调节心肌纤维化中胶原周转的主要分子之一。
