巨噬细胞极化在心肌梗死后的组织修复中起重要作用，M1型极化促进炎症反应，M2型极化增强组织修复。预实验发现：缺氧诱导有丝分裂因子(HIMF)在心梗组织表达增加，敲除HIMF基因降低梗死区M1炎症因子(NOS2、TNF-α等)、增加M2组织修复因子(ARG1等)表达，改善心功能；培养巨噬细胞过表达HIMF增加M1炎症因子，并降低组蛋白甲基化转移酶SUV39H1和其靶分子H3K9me3蛋白水平。H3K9me3在基因启动子区与HP1结合，抑制基因表达。因此设想：心梗时HIMF上调降低巨噬细胞SUV39H1表达，继而H3K9me3水平，解除H3K9me3和HP1对M1型炎症因子表达的抑制作用，促进M1极化所致炎症反应，抑制M2极化介导的组织修复，加重心梗损伤。拟构建巨噬细胞特异性HIMF敲除小鼠模型，采用染色质免疫沉淀、流式细胞、免疫组化等技术从分子、细胞和在体水平阐明心梗损伤机制和治疗新思路。

Ischemia induces irreversible injury of myocardium which must be efficiently repaired to maintain tissue integrity and ventricular contractile function. Macrophage polarization plays a critical role in tissue repair after myocardial infarction (MI). Initially, M1-like macrophages predominate within the infarct area, which induces inflammation and manifest phagocytic activity, facilitating elimination of damaged myocardium and setting the stage for tissue repair. Subsequently, the macrophages transform into reparative M2-like macrophages, fostering repair by promoting deposition of extracellular matrix proteins and angiogenesis and dampening inflammation. Abnormal increase in M1-phenotypic (inflammatory) function and impaired transformation to M2 (reparative) macrophages result in inefficient repair and catastrophic outcomes after MI. Our preliminary experiments demonstrated that hypoxia-induced mitogenic factor (HIMF) protein level was increased in infarcted heart tissues. Immunohistochemistry assay indicated co-localization of HIMF and CD68, a biomarker for macrophage in the infracted zone of MI. Ablation of HIMF gene decreased the infarct area and improved cardiac contractile function in mice exposed to MI. The damaging effect of HIMF appears to be associated with abnormal macrophage polarization since deficiency in HIMF decreased the mRNA levels of M1-like cytotoxic and inflammatory factors, including inducible nitric oxide synthase (NOS2), TNF-alpha and CCR2, and increased mRNA levels of M2-like reparative factor, arginase 1 and anti-inflammatory factor, IL-10 in infarct zones from MI mouse hearts. The effect of HIMF on enhancing M1-phenotypic function was confirmed in cultured macrophages, where HIMF overexpression in the cells increased the expression of M1-like cytotoxic and inflammatory factors, including NOS2, TNF-alpha, IL-6 and IL-1beta. Meanwhile, HIMF-overexpression decreased the the mRNA and protein levels of a histone methyltransferase, SUV39H1, and the protein level of trimethylation of histone H3 on lysine 9 (H3K9me3). H3K9me3 can interact with heterochromatin protein 1 (HP1) and promote transcriptional silencing. Based on the preliminary findings, we hypothesized that the upregulation of HIMF in MI decreases the expression of SUV39H1, resulting in decreased H3K9 trimethylation (H3K9me3). This effect relieves the suppression of H3K9me3 and HP1 on the transcription of M1-like genes and increases the expression of M1-like factors,leading to enhanced inflammatory response and impaired tissue repairment. Therefore, HIMF aggravates cardiac injury in MI by promoting M1-phenotypic transformation and subsequently dampening M2-phenotypic transformation in macrophages. To testify this hypothesis, we will construct macrophage-specific HIMF gene knockout mice and integrate multiple advanced techniques, such as chromatin immunoprecipitation (ChIP), flow cytometry, immunohistochemistry, gene manipulation, etc, to examine the effect of HIMF on macrophage polarization and the development of MI. Through these efforts, we try to find novel mechanisms underlying cardiac injury during MI relating to macrophage polarization and provide new therapeutic targets and strategies for the treatment of myocardial infarction.