Skeffington Katie L, Jones Ffion P, Suleiman M Saadeh, Caputo Massimo, Brancaccio Andrea, Bigotti Maria Giulia
Bristol Heart Institute, Research Floor Level 7, Bristol Royal Infirmary, Bristol, United Kingdom.
Institute of Chemical Sciences and Technologies "Giulio Natta" (SCITEC)-CNR, Rome, Italy.
Front Cardiovasc Med. 2022 Mar 9;9:813904. doi: 10.3389/fcvm.2022.813904. eCollection 2022.
Mature cardiomyocytes are unable to proliferate, preventing the injured adult heart from repairing itself. Studies in rodents have suggested that the extracellular matrix protein agrin promotes cardiomyocyte proliferation in the developing heart and that agrin expression is downregulated shortly after birth, resulting in the cessation of proliferation. Agrin based therapies have proven successful at inducing repair in animal models of cardiac injury, however whether similar pathways exist in the human heart is unknown.
Right ventricular (RV) biopsies were collected from 40 patients undergoing surgery for congenital heart disease and the expression of agrin and associated proteins was investigated.
Agrin transcripts were found in all samples and their levels were significantly negatively correlated to age ( = 0.026), as were laminin transcripts ( = 0.023), whereas no such correlation was found for the other proteins analyzed. No significant correlations for any of the proteins were found when grouping patients by their gender or pathology. Immunohistochemistry and western blots to detect and localize agrin and the other proteins under analysis in RV tissue, confirmed their presence in patients of all ages.
We show that agrin is progressively downregulated with age in human RV tissue but not as dramatically as has been demonstrated in mice; highlighting both similarities and differences to findings in rodents. Our results lay the groundwork for future studies exploring the potential of agrin-based therapies in the repair of damaged human hearts.
成熟心肌细胞无法增殖，这使得受伤的成年心脏无法自我修复。对啮齿动物的研究表明，细胞外基质蛋白聚集蛋白聚糖可促进发育中心脏的心肌细胞增殖，且出生后不久聚集蛋白聚糖的表达就会下调，导致增殖停止。基于聚集蛋白聚糖的疗法已在心脏损伤动物模型中成功诱导修复，然而人类心脏是否存在类似途径尚不清楚。
从40例接受先天性心脏病手术的患者中采集右心室（RV）活检样本，并研究聚集蛋白聚糖及相关蛋白的表达。
在所有样本中均发现了聚集蛋白聚糖转录本，其水平与年龄显著负相关（r = 0.026），层粘连蛋白转录本也是如此（r = 0.023），而在所分析的其他蛋白中未发现这种相关性。按性别或病理对患者进行分组时，未发现任何一种蛋白存在显著相关性。通过免疫组织化学和蛋白质印迹法检测并定位RV组织中的聚集蛋白聚糖及其他分析中的蛋白，证实它们在所有年龄段的患者中均存在。
我们表明，在人类RV组织中，聚集蛋白聚糖随年龄增长而逐渐下调，但不如在小鼠中所显示的那样显著；这突出了与啮齿动物研究结果的异同。我们的结果为未来探索基于聚集蛋白聚糖的疗法在修复受损人类心脏方面的潜力奠定了基础。
