PDF(Pubmed)
Abstract：
Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies. Empagliflozin (EMPA) improves cardiovascular outcomes in HFpEF patients, but the underlying mechanism remains elusive. Here, mice were fed a high-fat diet (HFD) supplemented with L-NAME for 12 weeks and subsequently intraperitoneally injected with EMPA for another 4 weeks. A 4D-DIA proteomic assay was performed to detect protein changes in the failing hearts. We identified 310 differentially expressed proteins (DEPs) (ctrl vs. HFpEF group) and 173 DEPs (HFpEF vs. EMPA group). The regulation of immune system processes was enriched in all groups and the interferon response genes (STAT1, Ifit1, Ifi35 and Ifi47) were upregulated in HFpEF mice but downregulated after EMPA administration. In addition, EMPA treatment suppressed the increase in the levels of aging markers (p16 and p21) in HFpEF hearts. Further bioinformatics analysis verified STAT1 as the hub transcription factor during pathological changes in HFpEF mice. We next treated H9C2 cells with IFN-γ, a primary agonist of STAT1 phosphorylation, to investigate whether EMPA plays a beneficial role by blocking STAT1 activation. Our results showed that IFN-γ treatment caused cardiomyocyte senescence and STAT1 activation, which were inhibited by EMPA administration. Notably, STAT1 inhibition significantly reduced cellular senescence possibly by regulating STING expression. Our findings revealed that EMPA mitigates cardiac inflammation and aging in HFpEF mice by inhibiting STAT1 activation. The STAT1-STING axis may act as a pivotal mechanism in the pathogenesis of HFpEF, especially under inflammatory and aging conditions.
摘要：
射血分数保留的心力衰竭（HFpEF）是一种致命的临床综合征，没有有效的治疗方法。Empagliflozin（EMPA）改善HFpEF患者的心血管结局，但是潜在的机制仍然难以捉摸。这里,给小鼠喂食补充有L-NAME的高脂肪饮食(HFD)12周,随后腹膜内注射EMPA,再注射4周.进行4D-DIA蛋白质组学测定以检测衰竭心脏中的蛋白质变化。我们鉴定了310种差异表达蛋白（DEP）（ctrl与HFpEF组）和173DEP（HFpEF与EMPA组）。在所有组中都富集了免疫系统过程的调节，并且在HFpEF小鼠中干扰素反应基因（STAT1，Ifit1，Ifi35和Ifi47）上调，但在EMPA施用后下调。此外,EMPA治疗抑制了HFpEF心脏中衰老标志物（p16和p21）水平的增加。进一步的生物信息学分析证实STAT1是HFpEF小鼠病理变化过程中的hub转录因子。我们接下来用IFN-γ处理H9C2细胞，STAT1磷酸化的主要激动剂，调查EMPA是否通过阻断STAT1激活发挥有益作用。我们的结果表明，IFN-γ治疗引起心肌细胞衰老和STAT1激活，被EMPA给药抑制。值得注意的是,STAT1抑制可能通过调节STING表达显著降低细胞衰老。我们的发现表明，EMPA通过抑制STAT1激活减轻HFpEF小鼠的心脏炎症和衰老。STAT1-STING轴可能是HFpEF发病机制中的一个重要机制,尤其是在炎症和衰老条件下。
