Garoffolo Gloria, Ferrari Silvia, De Martino Sara, Pizzo Emanuele, Candino Veronica, Curini Lavinia, Macrì Federica, Kruithof Boudewijn P T, Mongelli Alessia, Grillo Magda, Fanotti Nadia, Fejzaj Pamela, Casaburo Manuel, Alanazi Azizah, Marsan Nina Ajmone, Khaliel Feras, Alsulbud Ahmed, Agrifoglio Marco, Colombo Gualtiero I, Chiesa Mattia, Farsetti Antonella, Gaetano Carlo, Raucci Angela, Pesce Maurizio
Centro Cardiologico Monzino, IRCCS, Milan, Italy.
Consiglio Nazionale delle Ricerche, (CNR)-IASI "A. Ruberti", Rome, Italy.
Signal Transduct Target Ther. 2025 Sep 18;10(1):311. doi: 10.1038/s41392-025-02411-8.
Calcification of the aortic valve is a prevalent cardiovascular pathology in the aging population. Traditionally linked to inflammation, lipid accumulation, and risk conditions, this disease remains poorly understood, and effective treatments to halt its progression are not yet available. We hypothesized that calcification of the human valve interstitial cells (VICs) is associated with cellular senescence and alterations in the epigenetic setup, like in arteries. To verify this hypothesis, we examined the epigenetic marks (DNA methylation; Histones H3/H4 acetylation/methylation), the senescence and the calcification process in human VICs obtained from two distinct pathologic settings of the aortic valve (valve insufficiency and valve stenosis), and employed a mouse model of vascular/valve calcification, based on the administration of Vitamin D. Our findings revealed a link between the senescent phenotype of human VICs and calcification, characterized by increased DNA methylation and changes in histone epigenetic marks. To reverse the senescent/calcific VICs phenotype, we used Pentadecylidenemalonate-1b (SPV106), which activates KAT2B/pCAF histone acetyltransferase. In human VICs, SPV106 restored Histone acetylation marks, modified general chromatin accessibility and upregulated expression of Notch1, a potent inhibitor of valve calcification. The treatment also prevented the accumulation of calcific lesions in an ex vivo model of aortic valve calcification. In vivo treatment with SPV106 reduced calcification of the valve induced by administering Vitamin-D and positively preserved the valve motion compromised by calcification and the overall cardiac function. Based on these results, we propose the treatment with activators of histone acetylates as a viable option to prevent senescence/calcification of aortic VICs via restoration of correct chromatin acetylation, with concrete hopes to retard the progression of valve stenosis, a still largely unmet therapeutic need.
主动脉瓣钙化是老年人群中常见的心血管疾病。传统上，这种疾病与炎症、脂质堆积及风险因素相关，但人们对其仍知之甚少，且尚无有效方法阻止其进展。我们推测，人类瓣膜间质细胞（VICs）的钙化与细胞衰老及表观遗传状态改变有关，就像在动脉中一样。为验证这一假设，我们检测了从主动脉瓣两种不同病理状态（瓣膜关闭不全和瓣膜狭窄）获取的人类VICs中的表观遗传标记（DNA甲基化；组蛋白H3/H4乙酰化/甲基化）、衰老及钙化过程，并采用了基于维生素D给药的血管/瓣膜钙化小鼠模型。我们的研究结果揭示了人类VICs衰老表型与钙化之间的联系，其特征是DNA甲基化增加和组蛋白表观遗传标记的变化。为逆转衰老/钙化的VICs表型，我们使用了十五亚烷基丙二酸-1b（SPV106），它可激活KAT2B/pCAF组蛋白乙酰转移酶。在人类VICs中，SPV106恢复了组蛋白乙酰化标记，改变了一般染色质可及性，并上调了Notch1的表达，Notch1是瓣膜钙化的有效抑制剂。该治疗还在主动脉瓣钙化的体外模型中阻止了钙化病变的积累。SPV106的体内治疗减少了因给予维生素D诱导的瓣膜钙化，并积极维持了因钙化而受损的瓣膜运动及整体心脏功能。基于这些结果，我们提出用组蛋白乙酰化激活剂进行治疗是一种可行的选择，可通过恢复正确的染色质乙酰化来预防主动脉VICs的衰老/钙化，有望切实延缓瓣膜狭窄的进展，而瓣膜狭窄仍是一个很大程度上未满足的治疗需求。
