Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA USA.
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0310 Oslo, Norway; KG Jebsen Centre for B-Cell Malignancies, Institute for Clinical Medicine, University of Oslo, 0318 Oslo, Norway.
Matrix Biol. 2022 Jun;110:40-59. doi: 10.1016/j.matbio.2022.04.005. Epub 2022 Apr 22.
Heart failure is accompanied by adverse cardiac remodeling involving extracellular matrix (ECM). Cardiac ECM acts as a major reservoir for many proteins including growth factors, cytokines, collagens, and proteoglycans. Activated fibroblasts during cardiac injury can alter the composition and activity of these ECM proteins. Through unbiased analysis of a microarray dataset of human heart tissue comparing normal hearts (n = 135) to hearts with ischemic cardiomyopathy (n = 94), we identified Asporin (ASPN) as the top differentially regulated gene (DEG) in ischemic cardiomyopathy; its gene-ontology terms relate closely to fibrosis and cell death. ASPN is a Class I small leucine repeat protein member implicated in cancer, osteoarthritis, and periodontal ligament mineralization. However, its role in cardiac remodeling is still unknown. Here, we initially confirmed our big dataset analysis through cells, mice, and clinical atrial biopsy samples to demonstrate increased Aspn expression after pressure overload or cardiac ischemia/reperfusion injury. We tested the hypothesis that Aspn, being a TGFβ1 inhibitor, can attenuate fibrosis in mouse models of cardiac injury. We found that Aspn is released by cardiac fibroblasts and attenuates TGFβ signaling. Moreover, Aspn mice displayed increased fibrosis and decreased cardiac function after pressure overload by transverse aortic constriction (TAC) in mice. In addition, Aspn protected cardiomyocytes from hypoxia/reoxygenation-induced cell death and regulated mitochondrial bioenergetics in cardiomyocytes. Increased infarct size after ischemia/reperfusion injury in Aspn mice confirmed Aspn's contribution to cardiomyocyte viability. Echocardiography revealed greater reduction in left ventricular systolic function post-I/R in the Aspn animals compared to wild type. Furthermore, we developed an ASPN-mimic peptide using molecular modeling and docking which when administered to mice prevented TAC-induced fibrosis and preserved heart function. The peptide also reduced infarct size after I/R in mice, demonstrating the translational potential of ASPN-based therapy. Thus, we establish the role of ASPN as a critical ECM molecule that regulates cardiac remodeling to preserve heart function.
心力衰竭伴随着细胞外基质（ECM）的不良心脏重构。心脏 ECM 作为许多蛋白质的主要储存库，包括生长因子、细胞因子、胶原和蛋白聚糖。心脏损伤时激活的成纤维细胞可以改变这些 ECM 蛋白的组成和活性。通过对比较正常心脏（n=135）和缺血性心肌病心脏（n=94）的人类心脏组织微阵列数据集进行无偏分析，我们确定了天冬氨酸蛋白酶抑制剂（ASPN）是缺血性心肌病中差异调节基因（DEG）的首位；其基因本体论术语与纤维化和细胞死亡密切相关。ASPN 是一种 I 类小亮氨酸重复蛋白家族成员，与癌症、骨关节炎和牙周韧带矿化有关。然而，它在心脏重构中的作用尚不清楚。在这里，我们最初通过细胞、小鼠和临床心房活检样本验证了我们的大数据集分析，以证明压力超负荷或心脏缺血/再灌注损伤后 Aspn 表达增加。我们假设 Aspn 作为 TGFβ1 抑制剂可以减轻心脏损伤模型中的纤维化。我们发现 Aspn 由心脏成纤维细胞释放，并减弱 TGFβ 信号。此外，Aspn 小鼠在横主动脉缩窄（TAC）后压力超负荷时表现出纤维化增加和心脏功能下降。此外，Aspn 可保护心肌细胞免受缺氧/复氧诱导的细胞死亡，并调节心肌细胞中线粒体生物能。Aspn 小鼠缺血/再灌注损伤后的梗死面积增加证实了 Aspn 对心肌细胞活力的贡献。超声心动图显示 Aspn 动物在缺血/再灌注后左心室收缩功能的降低幅度大于野生型。此外，我们使用分子建模和对接开发了一种 ASPN 模拟肽，当将其施用于小鼠时，可预防 TAC 诱导的纤维化并维持心脏功能。该肽还可减少小鼠缺血/再灌注后的梗死面积，证明了基于 ASPN 的治疗的转化潜力。因此，我们确定了 ASPN 作为一种关键的细胞外基质分子的作用，该分子通过调节心脏重构来维持心脏功能。
