Wu Jiaqin, Wang Sixiang, Gao Pengfei, Wang Shunshun, Yu Huiming, Du Qianqian, Liu Minfu, Hou Shuwan, Jiang Shan, Xu Huajiao, Ye Siyi, Feng Fan, Wang Chunli, Xu Kang
National Innovation and Attracting Talents "111" Base, Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.
School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China.
Phytother Res. 2025 Jul;39(7):3212-3224. doi: 10.1002/ptr.8504. Epub 2025 Jun 8.
Calcific aortic valve disease (CAVD) is a common cardiovascular disorder. It is characterized by the thickening, fibrosis, and mineralization of aortic valve leaflets. These pathological changes can progress to heart failure if not managed effectively. Current surgical or transcatheter aortic valve replacement options exist, yet no pharmacotherapy has been established to impede CAVD advancement. Prior research by our team spotlighted the significance of lactate-derived protein lactylation (Kla) in initiating valve calcification. In this study, we aim to uncover the anti-calcification capacity of jatrorrhizine (JAT) and dissect its novel molecular underpinnings. The multi-omics analyses were used to indicate that JAT affects the glycolysis of hVICs, thus exerting a therapeutic effect on CAVD. Then, molecular docking, immunoprecipitation, and site mutation were used to demonstrate that JAT can reduce the lactylation of ALDOA at the K42 site by binding to the lactyltransferases KAT5, thereby affecting its enzymatic stability and downstream metabolic pathways. JAT impeded CAVD by perturbing glycolysis and Kla. Notably, a decline in non-histone Kla modification was linked to JAT inhibition of the osteogenic phenotype. ALDOA Kla, among glycolytic rate-limiting enzymes, is a prime target of JAT anti-calcification action. Crucially, the ALDOA K42la site was correlated with JAT-induced suppression of Runx2 expression. JAT treatment effectively curbed osteogenic differentiation in human aortic valve interstitial cells (hVICs) and mitigated CAVD progression in mice. our findings pioneer the revelation that JAT mitigates calcification by targeting ALDOA K42la to interfere with glycolysis, suggesting its potential as a potent preventative agent against CAVD. JAT alleviates calcific aortic valve disease via interfering with glycolysis targeting ALDOA K42 lactylation.
钙化性主动脉瓣疾病（CAVD）是一种常见的心血管疾病。其特征是主动脉瓣叶增厚、纤维化和矿化。如果不进行有效治疗，这些病理变化会发展为心力衰竭。目前存在外科手术或经导管主动脉瓣置换的选择，但尚未确立能够阻止CAVD进展的药物治疗方法。我们团队之前的研究突出了乳酸衍生的蛋白质乳酰化（Kla）在引发瓣膜钙化中的重要性。在本研究中，我们旨在揭示小檗碱（JAT）的抗钙化能力，并剖析其新的分子机制。多组学分析表明JAT影响人主动脉瓣间质细胞（hVICs）的糖酵解，从而对CAVD发挥治疗作用。然后，通过分子对接、免疫沉淀和位点突变证明JAT可通过与乳酰转移酶KAT5结合来减少ALDOA在K42位点的乳酰化，从而影响其酶稳定性和下游代谢途径。JAT通过干扰糖酵解和Kla来阻止CAVD。值得注意的是，非组蛋白Kla修饰的下降与JAT对成骨表型的抑制有关。在糖酵解限速酶中，ALDOA Kla是JAT抗钙化作用的主要靶点。至关重要的是，ALDOA K42la位点与JAT诱导的Runx2表达抑制相关。JAT治疗有效抑制了人主动脉瓣间质细胞（hVICs）的成骨分化，并减轻了小鼠CAVD的进展。我们的研究首次揭示JAT通过靶向ALDOA K42la干扰糖酵解来减轻钙化，表明其作为一种有效的CAVD预防药物的潜力。JAT通过干扰靶向ALDOA K42乳酰化的糖酵解来减轻钙化性主动脉瓣疾病。
