Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA.
Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
Biomater Sci. 2022 Nov 8;10(22):6341-6353. doi: 10.1039/d2bm00844k.
Aortic valve stenosis (AVS) is a sexually dimorphic cardiovascular disease that is driven by fibrosis and calcification of the aortic valve leaflets. Circulating inflammatory factors present in serum from AVS patients contribute to sex differences in valve fibro-calcification by driving the activation of valvular interstitial cells (VICs) to myofibroblasts and/or osteoblast-like cells. However, the molecular mechanisms by which inflammatory factors contribute to sex-specific valve fibro-calcification remain largely unknown. In this study, we identified inflammatory factors present in serum samples from AVS patients that regulate sex-specific myofibroblast activation and osteoblast-like differentiation. After correlating serum proteomic datasets with clinical and myofibroblast datasets, we identified annexin A2 and cystatin C as candidate inflammatory factors that correlate with both AVS patient severity and myofibroblast activation measurements Validation experiments utilizing hydrogel biomaterials as cell culture platforms that mimic the valve extracellular matrix confirmed that annexin A2 and cystatin C promote sex-specific VIC activation to myofibroblasts p38 MAPK signaling. Additionally, annexin A2 and cystatin C increase osteoblast-like differentiation primarily in male VICs. Our results implicate serum inflammatory factors as potential AVS biomarkers that also contribute to sexually dimorphic AVS progression by driving VIC myofibroblast activation and/or osteoblast-like differentiation. Collectively, the results herein further our overall understanding as to how biological sex may impact inflammation-driven AVS and may lead to the development of sex-specific drug treatment strategies.
主动脉瓣狭窄（AVS）是一种性别二态性心血管疾病，由主动脉瓣叶的纤维化和钙化驱动。来自 AVS 患者血清中的循环炎症因子通过驱动瓣膜间质细胞（VIC）向肌成纤维细胞和/或成骨样细胞的激活，导致瓣膜纤维钙化的性别差异。然而，炎症因子导致性别特异性瓣膜纤维钙化的分子机制在很大程度上仍不清楚。在这项研究中，我们鉴定了来自 AVS 患者血清样本中的炎症因子，这些因子调节性别特异性肌成纤维细胞激活和成骨样细胞分化。在将血清蛋白质组数据集与临床和肌成纤维细胞数据集相关联后，我们确定了 annexin A2 和半胱氨酸蛋白酶抑制剂 C 作为候选炎症因子，它们与 AVS 患者的严重程度和肌成纤维细胞激活测量值相关。利用水凝胶生物材料作为模拟瓣膜细胞外基质的细胞培养平台的验证实验证实，annexin A2 和半胱氨酸蛋白酶抑制剂 C 促进性别特异性 VIC 向肌成纤维细胞的激活和 p38 MAPK 信号。此外，annexin A2 和半胱氨酸蛋白酶抑制剂 C 主要增加男性 VIC 的成骨样分化。我们的研究结果表明，血清炎症因子可能是 AVS 的潜在生物标志物，通过驱动 VIC 肌成纤维细胞激活和/或成骨样细胞分化，也导致性别二态性 AVS 进展。总之，这些结果进一步增强了我们对生物学性别如何影响炎症驱动的 AVS 的整体理解，并可能导致针对性别特异性的药物治疗策略的发展。
