Ge Chaowen, Sun Hao, Wang Ning, Huang Ping
Anhui Province Key Laboratory of Chinese Medicinal Formula, Anhui University of Chinese Medicine, Hefei 230012, China; Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine, Anhui Academy of Chinese Medicine, Hefei 230012, China.
Anhui Province Key Laboratory of Chinese Medicinal Formula, Anhui University of Chinese Medicine, Hefei 230012, China; Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine, Anhui Academy of Chinese Medicine, Hefei 230012, China.
Phytomedicine. 2025 Sep;145:157011. doi: 10.1016/j.phymed.2025.157011. Epub 2025 Jun 18.
Hydroxysafflor yellow A (HSYA), the primary active constituent of Safflower, a traditional Chinese medicine, has demonstrated promising therapeutic potential in the treatment of cardiovascular and cerebrovascular injuries. However, the impact of HSYA on stroke-induced cardiac syndrome and the underlying mechanisms remain to be elucidated.
Laser super-resolution microscopy and transmission electron microscopy were employed to examine cerebral ischemic injury. Echocardiography and immunofluorescence techniques were utilized to assess cardiac function and inflammatory damage. Western blot analysis was conducted to measure the expression levels of apoptosis-related proteins in heart tissue.
HE revealed that SHS induced inflammatory infiltration in the myocardium. Echocardiographic findings indicated that SHS impaired cardiac function. ELISA results demonstrated that SHS led to elevated levels of norepinephrine and epinephrine. Transmission electron microscopy (TEM) observations confirmed that SHS resulted in mitochondrial damage within cardiac cells. Immunofluorescence analysis further showed that SHS facilitated the recruitment of cardiac macrophages, upregulated the expression of ZBP1 and NLRP3, and increased the production of inflammatory cytokines and inflammasomes. Co-immunoprecipitation experiments demonstrated that ZBP1 interacts with NLRP3. Inhibiting sympathetic overactivation exerts a protective effect on the heart. Furthermore, HSYA not only reversed the aforementioned conditions but also exerted protective effects on both cardiac and cerebral tissues. Immunofluorescence analysis revealed that HSYA inhibited the formation of the ZBP1 and NLRP3 complexes, as well as the inflammasome complex. Molecular docking studies indicated that HSYA and ZBP1 share the LYS-166 binding site, and protein docking results demonstrated that ZBP1 and NLRP3 also share this binding site. Mutations at this site diminished the protective efficacy of HSYA against SHS.
HSYA mitigates macrophage recruitment through the inhibition of the ZBP1-NLRP3 signaling pathway, thereby improving sympathetic nerve function, suppressing panoptosis, and alleviating SHS injury by competitively binding to the LYS-166 site of ZBP1 with NLRP3.
羟基红花黄色素A（HSYA）是中药红花的主要活性成分，在治疗心脑血管损伤方面已显示出有前景的治疗潜力。然而，HSYA对中风诱导的心脏综合征的影响及其潜在机制仍有待阐明。
采用激光超分辨率显微镜和透射电子显微镜检查脑缺血损伤。利用超声心动图和免疫荧光技术评估心脏功能和炎症损伤。进行蛋白质免疫印迹分析以测量心脏组织中凋亡相关蛋白的表达水平。
苏木精-伊红染色显示，中风诱导的心脏综合征（SHS）导致心肌炎症浸润。超声心动图结果表明，SHS损害心脏功能。酶联免疫吸附测定结果表明，SHS导致去甲肾上腺素和肾上腺素水平升高。透射电子显微镜观察证实，SHS导致心脏细胞内线粒体损伤。免疫荧光分析进一步表明，SHS促进心脏巨噬细胞募集，上调ZBP1和NLRP3的表达，并增加炎性细胞因子和炎性小体的产生。免疫共沉淀实验表明，ZBP1与NLRP3相互作用。抑制交感神经过度激活对心脏具有保护作用。此外，HSYA不仅逆转了上述情况，还对心脏和脑组织均发挥保护作用。免疫荧光分析显示，HSYA抑制ZBP1和NLRP3复合物以及炎性小体复合物的形成。分子对接研究表明，HSYA和ZBP1共享LYS-166结合位点，蛋白质对接结果表明，ZBP1和NLRP3也共享该结合位点。该位点的突变降低了HSYA对SHS的保护功效。
HSYA通过抑制ZBP1-NLRP3信号通路减轻巨噬细胞募集，从而改善交感神经功能，抑制全细胞凋亡，并通过与NLRP3竞争性结合ZBP1的LYS-166位点减轻SHS损伤。
