Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina.
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.
Am J Physiol Heart Circ Physiol. 2021 Feb 1;320(2):H604-H612. doi: 10.1152/ajpheart.00552.2020. Epub 2020 Dec 11.
In human heart failure and in murine hearts with left-ventricular pressure overload (LVPO), increases in fibrosis are associated with increases in myocardial stiffness. Secreted protein acidic and rich in cysteine (SPARC) is shown to be necessary for both cardiac fibrosis and increases in myocardial stiffness in response to LVPO; however, cellular sources of cardiac SPARC are incompletely defined. Irradiation and bone marrow transfer were undertaken to test the hypothesis that SPARC expression by bone marrow-derived cells is an important mediator of fibrosis in LVPO. In recipient SPARC-null mice transplanted with donor wild-type (WT) bone marrow and subjected to LVPO, levels of fibrosis similar to that of WT mice were found despite the lack of SPARC expression by resident cells. In recipient WT mice with donor SPARC-null bone marrow, significantly less fibrosis versus that of WT mice was found despite the expression of SPARC by resident cells. Increases in myocardial stiffness followed a similar pattern to that of collagen deposition. Myocardial macrophages were significantly reduced in SPARC-null mice with LVPO versus that of WT mice. Recipient SPARC-null mice transplanted with donor WT bone marrow exhibited an increase in cardiac macrophages versus that of SPARC-null LVPO and donor WT mice with recipient SPARC-null bone marrow. Expression of vascular cellular adhesion molecule (VCAM), a previously identified binding partner of SPARC, was assessed in all groups and with the exception of WT mice, increases in VCAM immunoreactivity with LVPO were observed. However, no differences in VCAM expression between bone marrow transplant groups were noted. In conclusion, SPARC expression by bone marrow-derived cells was critical for fibrotic deposition of collagen and influenced the expansion of myocardial macrophages in response to LVPO. Myocardial fibrosis and the resultant increases in LV and myocardial stiffness represent pivotal consequences of chronic pressure overload (PO). In this study, a murine model of cardiac fibrosis induced by PO was used to demonstrate a critical function of SPARC in bone marrow-derived cells that drives cardiac fibrosis and increases in cardiac macrophages.
在人类心力衰竭和左心室压力超负荷（LVPO）的小鼠心脏中，纤维化的增加与心肌僵硬的增加有关。已表明富含半胱氨酸的酸性分泌蛋白（SPARC）对于 LVPO 引起的心脏纤维化和心肌僵硬的增加都是必需的；然而，心脏 SPARC 的细胞来源尚未完全确定。进行了辐照和骨髓转移，以检验骨髓来源的细胞中 SPARC 的表达是 LVPO 中纤维化的重要介质的假设。在接受野生型（WT）骨髓移植的 SPARC 敲除（KO）受体小鼠中进行 LVPO 后，尽管驻留细胞缺乏 SPARC 表达，但发现纤维化水平与 WT 小鼠相似。在具有 SPARC KO 供体骨髓的 WT 受体小鼠中，尽管驻留细胞表达 SPARC，但发现纤维化程度明显低于 WT 小鼠。心肌僵硬的增加遵循与胶原蛋白沉积相似的模式。与 WT 小鼠相比，LVPO 中的 SPARC KO 小鼠中的心肌巨噬细胞明显减少。与 SPARC KO LVPO 和 SPARC KO WT 供体小鼠相比，接受 WT 供体骨髓移植的 SPARC KO 受体小鼠中的心脏巨噬细胞增加。评估了所有组中的血管细胞黏附分子（VCAM）的表达，VCAM 是 SPARC 的先前鉴定的结合伴侣，除了 WT 小鼠之外，观察到 VCAM 免疫反应性随 LVPO 增加。然而，在骨髓移植组之间未注意到 VCAM 表达的差异。总之，骨髓来源的细胞中 SPARC 的表达对于胶原蛋白的纤维沉积至关重要，并影响 LVPO 后心肌巨噬细胞的扩张。心肌纤维化和由此导致的 LV 和心肌僵硬增加是慢性压力超负荷（PO）的关键后果。在这项研究中，使用 PO 诱导的心脏纤维化的小鼠模型来证明 SPARC 在驱动心脏纤维化和增加心脏巨噬细胞的骨髓来源细胞中的关键作用。
