SPARC production by bone marrow-derived cells contributes to myocardial fibrosis in pressure overload
SPARC production by bone marrow-derived cells contributes to myocardial fibrosis in pressure overload
复制标题
DOI：
10.1152/ajpheart.00552.2020
复制
发表时间：
2021-02-01
影响因子：
4.8
通讯作者：
Bradshaw, Amy D.
中科院分区：
文献类型：
--
作者：
Riley, Hannah J.;Kelly, Ryan R.;Bradshaw, Amy D.
在人类心力衰竭和左心室压力过载（LVPO）的小鼠心脏中，纤维化的增加与心肌硬度的增加相关。酸性和富含半胱氨酸的分泌蛋白（SPARC）被证明是心肌纤维化和心肌僵硬增加对LVPO反应所必需的；然而，心脏SPARC的细胞来源尚未完全确定。通过照射和骨髓移植来验证骨髓源性细胞的SPARC表达是LVPO纤维化的重要介质这一假设。在用供体野生型（WT）骨髓移植并进行LVPO的受体SPARC缺失小鼠中，尽管驻留细胞缺乏SPARC表达，但发现其纤维化水平与WT小鼠相似。在供体无SPARC骨髓的受体WT小鼠中，尽管驻留细胞表达SPARC，但与WT小鼠相比，纤维化明显减少。心肌硬度的增加遵循与胶原沉积相似的模式。与WT小鼠相比，LVPO使SPARC-null小鼠心肌巨噬细胞明显减少。与sparc缺失的LVPO和移植了sparc缺失骨髓的供体WT小鼠相比，移植了供体WT骨髓的受体sparc缺失小鼠的心脏巨噬细胞增加。血管细胞粘附分子（vascular cellular adhesion molecule， VCAM）是先前确定的SPARC的结合伙伴，在所有组中均进行了表达评估，除WT小鼠外，观察到VCAM与LVPO的免疫反应性增加。然而，骨髓移植组间VCAM的表达没有差异。综上所述，骨髓源性细胞的SPARC表达对胶原的纤维化沉积至关重要，并影响心肌巨噬细胞对LVPO的反应。心肌纤维化和由此引起的左室电压升高和心肌僵硬度是慢性压力过载（PO）的关键后果。在这项研究中，使用了PO诱导的小鼠心脏纤维化模型来证明SPARC在骨髓源性细胞中的关键功能，该功能驱动心脏纤维化和心脏巨噬细胞的增加。
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.NEW & NOTEWORTHY 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.