Kachanova O S, Boyarskaya N V, Docshin P M, Scherbinin T S, Zubkova V G, Saprankov V L, Uspensky V E, Mitrofanova L B, Malashicheva A B
Research Laboratory of Diseases with Excessive Calcification, Almazov National Medical Research Centre, Saint Petersburg, Russia.
Front Cardiovasc Med. 2024 Aug 29;11:1411398. doi: 10.3389/fcvm.2024.1411398. eCollection 2024.
The development of drug therapy for the pathological calcification of the aortic valve is still an open issue due to the lack of effective treatment strategies. Currently, the only option for treating this condition is surgical correction and symptom management. The search for models to study the safety and efficacy of anti-calcifying drugs requires them to not only be as close as possible to conditions, but also to be flexible with regard to the molecular studies that can be applied to them. The model has several advantages, including the ability to study the effect of a drug on human cells while preserving the original structure of the valve. This allows for a better understanding of how different cell types interact within the valve, including non-dividing cells. The aim of this study was to develop a reproducible calcification model based on valves from patients with calcific aortic stenosis. We aimed to induce spontaneous calcification in valve tissue fragments under osteogenic conditions, and to demonstrate the possibility of significantly suppressing it using a calcification inhibitor. To validate the model, we tested a Notch inhibitor Crenigacestat (LY3039478), which has been previously shown to have an anti-calcifying effect on interstitial cell of the aortic valve. We demonstrate here an approach to testing calcification inhibitors using an model of cultured human aortic valve tissue fragments. Thus, we propose that models may warrant further investigation for their utility in studying aortic valve disease and performing pre-clinical assessment of drug efficacy.
由于缺乏有效的治疗策略，主动脉瓣病理性钙化的药物治疗发展仍然是一个未解决的问题。目前，治疗这种疾病的唯一选择是手术矫正和症状管理。寻找用于研究抗钙化药物安全性和有效性的模型，要求这些模型不仅要尽可能接近真实情况，而且在可应用于它们的分子研究方面要有灵活性。该模型有几个优点，包括能够在保留瓣膜原始结构的同时研究药物对人类细胞的作用。这有助于更好地理解不同细胞类型在瓣膜内的相互作用，包括非分裂细胞。本研究的目的是基于钙化性主动脉瓣狭窄患者的瓣膜开发一种可重复的钙化模型。我们旨在在成骨条件下诱导瓣膜组织碎片发生自发性钙化，并证明使用钙化抑制剂显著抑制钙化的可能性。为了验证该模型，我们测试了一种Notch抑制剂Crenigacestat（LY3039478），该抑制剂先前已被证明对主动脉瓣间质细胞有抗钙化作用。我们在此展示了一种使用培养的人主动脉瓣组织碎片模型测试钙化抑制剂的方法。因此，我们认为该模型在研究主动脉瓣疾病和进行药物疗效的临床前评估方面的实用性可能值得进一步研究。
