Ko Seien, Liu Xueyuan, Taniguchi Yurika, Ichihara Genki, Komuro Jin, Yamakawa Hiroyuki, Shirakawa Kohsuke, Hashimoto Hisayuki, Katsumata Yoshinori, Endo Jin, Hattori Masakazu, Minato Nagahiro, Sano Motoaki, Anzai Atsushi, Ieda Masaki
Department of Cardiology (S.K., X.L., Y.T., G.I., J.K., H.Y., K.S., H.H., Y.K., J.E., M.S., A.A., M.I.), Keio University School of Medicine, Tokyo, Japan.
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Japan (J.K.).
Circ Res. 2025 Aug;137(4):533-547. doi: 10.1161/CIRCRESAHA.124.326030. Epub 2025 Jun 26.
Sipa1 (signal-induced proliferation-associated gene 1) is known as a specific Rap1 (Ras-related protein 1) GTPase-activating protein that negatively regulates Rap1 signaling. Although Sipa1 has been extensively studied in cancer research, its role in the wound-healing response after myocardial infarction (MI) remains unexplored.
To investigate the role of endogenous Sipa1 in MI, we performed permanent left anterior descending artery ligation in both knockout mice and their control littermates. Bone marrow transplantation, flow cytometry, cell sorting, and transcriptomic analysis were conducted to identify the cellular source of Sipa1 in the infarcted heart. The role of cardiac fibroblast-derived Sipa1 during MI was examined using Sipa1 deletion approaches, specifically in cardiac fibroblasts, in vivo and in vitro.
Mice deficient in exhibited improved post-MI survival and cardiac function, along with attenuated expression of inflammatory mediators and diminished accumulation of Ly6C (lymphocyte antigen 6 complex, locus C) monocytes and CCR (C-C chemokine receptor) 2 macrophages in the infarcted heart. Although Sipa1 was broadly expressed in the heart, cardiac fibroblasts were responsible for the Sipa1-induced deleterious phenotype as demonstrated by cardiac fibroblast-specific conditional knockout mice, which averted excessive inflammation and adverse cardiac remodeling following MI. Mechanistically, Sipa1 promotes the production of CCL (C-C chemokine ligand) 2, CCL7, and GM-CSF (granulocyte/macrophage colony-stimulating factor) in the cardiac fibroblasts early after MI via a noncanonical RasGRP2 (Ras guanine nucleotide-releasing protein 2)-Ras-JNK (cellular Jun N-terminal kinase) signaling pathway, irrespective of canonical Rap1, thereby facilitating the accumulation and activation of inflammatory monocytes and macrophages.
These results identify a previously unknown fibroblast-myeloid axis characterized by Sipa1, which initiates excessive inflammation and leads to poor outcomes after MI. Targeting Sipa1 offers a potential novel therapeutic strategy to optimize post-MI wound-healing response, thereby preventing the development of chronic ischemic heart failure.
Sipa1（信号诱导增殖相关基因1）是一种特异性的Rap1（Ras相关蛋白1）GTP酶激活蛋白，对Rap1信号传导起负调节作用。尽管Sipa1在癌症研究中已得到广泛研究，但其在心肌梗死（MI）后伤口愈合反应中的作用仍未被探索。
为了研究内源性Sipa1在心肌梗死中的作用，我们对基因敲除小鼠及其对照同窝小鼠进行了永久性左冠状动脉前降支结扎。通过骨髓移植、流式细胞术、细胞分选和转录组分析来确定梗死心脏中Sipa1的细胞来源。使用Sipa1缺失方法，特别是在体内和体外对心脏成纤维细胞中Sipa1缺失的方法，来研究心肌梗死期间心脏成纤维细胞衍生的Sipa1的作用。
基因缺失的小鼠在心肌梗死后存活率提高，心脏功能改善，梗死心脏中炎症介质的表达减弱，Ly6C（淋巴细胞抗原6复合体，C位点）单核细胞和CCR（C-C趋化因子受体）2巨噬细胞的积累减少。尽管Sipa1在心脏中广泛表达，但心脏成纤维细胞特异性条件性基因敲除小鼠证明，心脏成纤维细胞是Sipa1诱导有害表型的原因，该基因敲除小鼠可避免心肌梗死后过度炎症和不良心脏重塑。机制上，心肌梗死后早期，Sipa1通过非经典的RasGRP2（Ras鸟嘌呤核苷酸释放蛋白2）-Ras-JNK（细胞Jun N端激酶）信号通路促进心脏成纤维细胞中CCL（C-C趋化因子配体）2、CCL7和GM-CSF（粒细胞/巨噬细胞集落刺激因子）的产生，而不依赖经典的Rap信号，从而促进炎症单核细胞和巨噬细胞的积累和激活。
这些结果确定了一个以前未知的以Sipa1为特征的成纤维细胞-髓系轴，该轴引发过度炎症并导致心肌梗死后预后不良。靶向Sipa1提供了一种潜在的新型治疗策略，以优化心肌梗死后的伤口愈合反应，从而预防慢性缺血性心力衰竭的发展。
