Department of Cardiology and Angiology I, University Heart Center Freiburg - Bad Krozingen, Medical Faculty, University of Freiburg, Hugstetterstr. 55, 79106, Freiburg, Germany.
Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany.
Basic Res Cardiol. 2022 Mar 30;117(1):16. doi: 10.1007/s00395-022-00927-6.
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 P2Y-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 P2Y. 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 P2Y in LSK, implicating a direct effect of ADP on LSK via P2Y signaling. P2Y knockout and P2Y 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, P2Y inhibition preserved cardiac function and reduced chronic adverse cardiac remodeling after MI. P2Y-dependent signaling is involved in emergency hematopoiesis after MI and fuels post-ischemic inflammation, proposing a novel, non-canonical value for P2Y antagonists beyond inhibition of platelet-mediated atherothrombosis.
应急造血是心肌梗死（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，并为局部细胞募集到梗死部位补充白细胞供应。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 介导的信号转导对 MI 后应急造血和心脏重塑的影响。通过在小鼠模型中进行永久性冠状动脉结扎来诱导 MI。使用血小板特异性基因敲除和 P2Y 的药理学抑制模型评估 BM 激活、炎症细胞组成和心脏功能。补充的体外研究允许研究 ADP 对 LSK 细胞的依赖作用。我们发现 ADP 作为造血 BM 的危险信号，通过促进 Akt 磷酸化和细胞周期进程来促进应急造血。我们能够在 LSK 中检测到 P2Y，这表明 ADP 通过 P2Y 信号直接作用于 LSK。P2Y 敲除和普拉格雷的 P2Y 抑制剂治疗减少了 MI 后的应急造血和过度炎症反应，导致血液和梗死部位下游祖细胞和炎症细胞数量减少。最终，P2Y 抑制可保护心脏功能并减少 MI 后的慢性不良心脏重塑。MI 后应急造血中涉及 P2Y 依赖性信号转导，并为 P2Y 拮抗剂除抑制血小板介导的动脉血栓形成外提供了新的、非经典的价值。
