Asporin, an extracellular matrix protein, is a beneficial regulator of cardiac remodeling.
Asporin, an extracellular matrix protein, is a beneficial regulator of cardiac remodeling.
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DOI：
10.1016/j.matbio.2022.04.005
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发表时间：
2022-06
期刊：
影响因子：
6.9
通讯作者：
Piplani, Honit
中科院分区：
文献类型：
--
作者：
Huang, Chengqun;Sharma, Ankush;Thakur, Reetu;Rai, Deepika;Katiki, Madhusudhanarao;Germano, Juliana de Freitas;Song, Yang;Singh, Sakshi;Sin, Jon;Sengstock, David;Andres, Allen M.;Murali, Ramachandran;Mentzer, Robert M.;Gottlieb, Roberta A.;Piplani, Honit
心力衰竭伴随着涉及细胞外基质（ECM）的不良心脏重塑。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。在心脏损伤过程中激活的成纤维细胞可以改变这些ECM蛋白的组成和活性。通过对人类心脏组织微阵列数据集的无偏分析，将正常心脏（n = 135）与缺血性心肌病心脏（n = 94）进行比较，我们确定Asprin（ASPN）为缺血性心肌病中的顶级差异调节基因（DEG）;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，与癌症、骨关节炎和牙周膜矿化有关。然而，其在心脏重塑中的作用仍然未知。在这里，我们最初通过细胞、小鼠和临床心房活检样本证实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。我们验证了Aspn作为TGF β 1抑制剂可以减轻小鼠心脏损伤模型中的纤维化的假设。我们发现Aspn由心脏成纤维细胞释放并减弱TGF β信号传导。此外，Aspn −/−小鼠在通过小鼠横主动脉缩窄（TAC）造成的压力超负荷后显示出纤维化增加和心脏功能下降。此外，Aspn保护心肌细胞免于缺氧/再氧合诱导的细胞死亡并调节心肌细胞中的线粒体生物能量学。Aspn −/−小鼠缺血/再灌注损伤后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，与野生型相比，Aspn −/−动物I/R后左心室收缩功能降低更大。此外，我们使用分子建模和对接开发了ASPN模拟肽，当给予小鼠时，其防止TAC诱导的纤维化并保留心脏功能。该肽还减少了小鼠I/R后的梗死面积，证明了基于ASPN的治疗的转化潜力。因此，我们建立了ASPN作为一种重要的ECM分子的作用，它调节心脏重塑以保护心脏功能。
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.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
3.7
作者：
Huang C;Andres AM;Ratliff EP;Hernandez G;Lee P;Gottlieb RA
通讯作者：
Gottlieb RA
影响因子：
5
作者：
Bowers SL;Banerjee I;Baudino TA
通讯作者：
Baudino TA
影响因子：
5.4
作者：
Hall C;Gehmlich K;Denning C;Pavlovic D
通讯作者：
Pavlovic D
影响因子：
3.7
作者：
Autiero I;Costantini S;Colonna G
通讯作者：
Colonna G