Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
J Thorac Cardiovasc Surg. 2013 Dec;146(6):1516-25. doi: 10.1016/j.jtcvs.2013.02.045.
Remodeling of the left ventricle (LV) in idiopathic dilated cardiomyopathy (IDCM) is known to be associated with multiple pathologic changes that endogenous factors, such as hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), protect against. Although a clinically relevant delivery method of these factors has not been established, ONO1301, a synthetic prostacyclin agonist, has been shown to upregulate multiple cardioprotective factors, including HGF and VEGF, in vivo. We thus hypothesized that ONO1301 may reverse LV remodeling in the DCM heart.
ONO1301 dose-dependently added to the normal human dermal fibroblasts and human coronary artery smooth muscle cells in vitro, to measure the expression of HGF, VEGF, stromal cell-derived factor (SDF)-1, and granulocyte-colony stimulating factor (G-CSF), assessed by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. δ-Sarcoglycan-deficient J2N-k hamsters, which is an established DCM model, were treated by epicardial implantation of an atelocollagen sheet with or without ONO1301 immersion or sham operation.
ONO1301 dose-dependently upregulated expression of these 4 factors in vitro. ONO1301 treatment, which induced dominant elevation of ONO1301 levels for 2 weeks, significantly preserved cardiac performance and prolonged survival compared with the other groups. This treatment significantly upregulated expressions of cardioprotective factors and was associated with increased capillaries, attenuated fibrosis, and upregulation of α-sarcoglycan in the DCM heart.
ONO1301 atelocollagen-sheet implantation reorganized cytoskeletal proteins, such as α-sarcoglycan, increased capillaries, reduced fibrosis, and was associated with upregulated expression of multiple cardioprotective factors, leading to preservation of cardiac performance and prolongation of survival in the δ-sarcoglycan-deficient DCM hamster.
已知特发性扩张型心肌病（IDCM）的左心室（LV）重构与多种病理变化有关，这些变化由内源性因子如肝细胞生长因子（HGF）和血管内皮生长因子（VEGF）来保护。虽然这些因子的临床相关传递方法尚未建立，但合成前列环素激动剂 ONO1301 已被证明可在体内上调多种心肌保护因子，包括 HGF 和 VEGF。因此，我们假设 ONO1301 可能逆转 DCM 心脏的 LV 重构。
ONO1301 以剂量依赖的方式添加到正常的人真皮成纤维细胞和人冠状动脉平滑肌细胞中，通过实时聚合酶链反应（PCR）和酶联免疫吸附试验（ELISA）测量 HGF、VEGF、基质细胞衍生因子（SDF）-1 和粒细胞集落刺激因子（G-CSF）的表达。δ-横纹肌营养不良 J2N-k 仓鼠是一种已建立的 DCM 模型，通过心包内植入含有或不含有 ONO1301 浸泡的去端胶原片或假手术进行治疗。
ONO1301 以剂量依赖的方式上调了这 4 种因子的表达。ONO1301 治疗 2 周可诱导 ONO1301 水平显著升高，与其他组相比，可显著改善心脏功能并延长存活时间。这种治疗方法显著上调了心肌保护因子的表达，同时增加了毛细血管，减少了纤维化，并上调了 DCM 心脏中的α-横纹肌营养不良蛋白。
ONO1301 去端胶原片植入可重新组织细胞骨架蛋白，如α-横纹肌营养不良蛋白，增加毛细血管，减少纤维化，并与多种心肌保护因子的表达上调有关，从而改善δ-横纹肌营养不良蛋白缺陷的 DCM 仓鼠的心脏功能并延长其存活时间。
