Zhang Shuang, Bories Gael, Lantz Connor, Emmons Russel, Becker Amanda, Liu Esther, Abecassis Michael M, Yvan-Charvet Laurent, Thorp Edward B
Departments of Pathology and Pediatrics, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
UMR INSERM U1065/UNS, C3M, Bâtiment Universitaire ARCHIMED, Nice, France.
Front Cardiovasc Med. 2019 Apr 11;6:42. doi: 10.3389/fcvm.2019.00042. eCollection 2019.
Cardiovascular disease remains the leading cause of death worldwide. Myocardial ischemia is a major contributor to cardiovascular morbidity and mortality. In the case of acute myocardial infarction, subsequent cardiac repair relies upon the acute, and coordinated response to injury by innate myeloid phagocytes. This includes neutrophils, monocytes, macrophage subsets, and immature dendritic cells. Phagocytes function to remove necrotic cardiomyocytes, apoptotic inflammatory cells, and to remodel extracellular matrix. These innate immune cells also secrete cytokines and growth factors that promote tissue replacement through fibrosis and angiogenesis. Within the injured myocardium, macrophages polarize from pro-inflammatory to inflammation-resolving phenotypes. At the core of this functional plasticity is cellular metabolism, which has gained an appreciation for its integration with phagocyte function and remodeling of the transcriptional and epigenetic landscape. Immunometabolic rewiring is particularly relevant after ischemia and clinical reperfusion given the rapidly changing oxygen and metabolic milieu. Hypoxia reduces mitochondrial oxidative phosphorylation and leads to increased reliance on glycolysis, which can support biosynthesis of pro-inflammatory cytokines. Reoxygenation is permissive for shifts back to mitochondrial metabolism and fatty acid oxidation and this is ultimately linked to pro-reparative macrophage polarization. Improved understanding of mechanisms that regulate metabolic adaptations holds the potential to identify new metabolite targets and strategies to reduce cardiac damage through nutrient signaling.
心血管疾病仍然是全球主要的死亡原因。心肌缺血是心血管疾病发病率和死亡率的主要促成因素。在急性心肌梗死的情况下，随后的心脏修复依赖于先天性髓样吞噬细胞对损伤的急性协调反应。这包括中性粒细胞、单核细胞、巨噬细胞亚群和未成熟树突状细胞。吞噬细胞的功能是清除坏死的心肌细胞、凋亡的炎症细胞，并重塑细胞外基质。这些先天性免疫细胞还分泌细胞因子和生长因子，通过纤维化和血管生成促进组织替代。在受损心肌内，巨噬细胞从促炎表型转变为炎症消退表型。这种功能可塑性的核心是细胞代谢，它因其与吞噬细胞功能以及转录和表观遗传格局重塑的整合而受到重视。鉴于氧和代谢环境的快速变化，免疫代谢重编程在缺血和临床再灌注后尤为重要。缺氧会降低线粒体氧化磷酸化，并导致对糖酵解的依赖性增加，糖酵解可支持促炎细胞因子的生物合成。再灌注有利于向线粒体代谢和脂肪酸氧化转变，这最终与促修复性巨噬细胞极化有关。对调节代谢适应机制的深入理解有可能识别新的代谢物靶点和通过营养信号减少心脏损伤的策略。
