Emergency hematopoiesis is the driving force of the inflammatory response to myocardial infarction (MI). Increased proliferation of hematopoietic stem and progenitor cells (LSK) after MI enhances cell production in the bone marrow (BM) and replenishes leukocyte supply for local cell recruitment to the infarct. Decoding the regulation of the inflammatory cascade after MI may provide new avenues to improve post-MI remodeling. In this study, we describe the influence of adenosine diphosphate (ADP)-dependent P2Y₁₂-mediated signaling on emergency hematopoiesis and cardiac remodeling after MI. Permanent coronary ligation was performed to induce MI in a murine model. BM activation, inflammatory cell composition and cardiac function were assessed using global and platelet-specific gene knockout and pharmacological inhibition models for P2Y₁₂. Complementary in vitro studies allowed for investigation of ADP-dependent effects on LSK cells. We found that ADP acts as a danger signal for the hematopoietic BM and fosters emergency hematopoiesis by promoting Akt phosphorylation and cell cycle progression. We were able to detect P2Y₁₂ in LSK, implicating a direct effect of ADP on LSK via P2Y₁₂ signaling. P2Y₁₂ knockout and P2Y₁₂ inhibitor treatment with prasugrel reduced emergency hematopoiesis and the excessive inflammatory response to MI, translating to lower numbers of downstream progeny and inflammatory cells in the blood and infarct. Ultimately, P2Y₁₂ inhibition preserved cardiac function and reduced chronic adverse cardiac remodeling after MI. P2Y₁₂-dependent signaling is involved in emergency hematopoiesis after MI and fuels post-ischemic inflammation, proposing a novel, non-canonical value for P2Y₁₂ antagonists beyond inhibition of platelet-mediated atherothrombosis.

紧急造血是心肌梗死 (MI) 炎症反应的驱动力。MI 后造血干细胞和祖细胞 (LSK) 的增殖增加，增强了骨髓 (BM) 中的细胞生成，并补充了白细胞供应，用于向梗塞部位募集局部细胞。解码 MI 后炎症级联的调节可能为改善 MI 后重塑提供新途径。在这项研究中，我们描述了二磷酸腺苷 (ADP) 依赖性 P2Y _12的影响-介导的心肌梗死后紧急造血和心脏重塑的信号传导。在小鼠模型中进行永久性冠状动脉结扎以诱导 MI。_{使用 P2Y 12}的全局和血小板特异性基因敲除和药理学抑制模型评估 BM 激活、炎症细胞组成和心脏功能。补充性体外研究允许研究 ADP 依赖性对 LSK 细胞的影响。我们发现 ADP 作为造血 BM 的危险信号，并通过促进 Akt 磷酸化和细胞周期进程促进紧急造血。我们能够在 LSK 中检测到 P2Y _{12 ，这表明 ADP 通过 P2Y 12}信号对 LSK 产生直接影响。P2Y ₁₂淘汰赛和 P2Y ₁₂普拉格雷抑制剂治疗减少了紧急造血和对 MI 的过度炎症反应，转化为血液和梗塞中下游后代和炎症细胞数量的减少。最终，抑制 P2Y ₁₂可以保护心脏功能并减少 MI 后慢性不良心脏重塑。P2Y _{12依赖性信号转导参与 MI 后的紧急造血并助长缺血后炎症，提出了 P2Y 12}拮抗剂在抑制血小板介导的动脉粥样硬化血栓形成之外的新的非规范价值。