Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, United States of America; Mississippi Center for Obesity Research, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, United States of America.
Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, United States of America.
J Mol Cell Cardiol. 2021 Sep;158:38-48. doi: 10.1016/j.yjmcc.2021.05.008. Epub 2021 May 21.
Myocardial infarction (MI) is one of the leading causes of mortality and cardiovascular disease worldwide. MI is characterized by a substantial inflammatory response in the infarcted left ventricle (LV), followed by transition of quiescent fibroblasts to active myofibroblasts, which deposit collagen to form the reparative scar. Metabolic shifting between glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) is an important mechanism by which these cell types transition towards reparative phenotypes. Thus, we hypothesized that dimethyl fumarate (DMF), a clinically approved anti-inflammatory agent with metabolic actions, would improve post-MI remodeling via modulation of macrophage and fibroblast metabolism. Adult male C57BL/6J mice were treated with DMF (10 mg/kg) for 3-7 days after MI. DMF attenuated LV infarct and non-infarct wall thinning at 3 and 7 days post-MI, and decreased LV dilation and pulmonary congestion at day 7. DMF improved LV infarct collagen deposition, myofibroblast activation, and angiogenesis at day 7. DMF also decreased pro-inflammatory cytokine expression (Tnf) 3 days after MI, and decreased inflammatory markers in macrophages isolated from the infarcted heart (Hif1a, Il1b). In fibroblasts extracted from the infarcted heart at day 3, RNA-Seq analysis demonstrated that DMF promoted an anti-inflammatory/pro-reparative phenotype. By Seahorse analysis, DMF did not affect glycolysis in either macrophages or fibroblasts at day 3, but enhanced macrophage OXPHOS while impairing fibroblast OXPHOS. Our results indicate that DMF differentially affects macrophage and fibroblast metabolism, and promotes anti-inflammatory/pro-reparative actions. In conclusion, targeting cellular metabolism in the infarcted heart may be a promising therapeutic strategy.
心肌梗死（MI）是全球范围内导致死亡和心血管疾病的主要原因之一。MI 的特征是在梗死的左心室（LV）中发生大量炎症反应，随后静止的成纤维细胞向活跃的肌成纤维细胞转化，肌成纤维细胞沉积胶原蛋白形成修复性瘢痕。糖酵解和线粒体氧化磷酸化（OXPHOS）之间的代谢转换是这些细胞类型向修复表型转化的重要机制。因此，我们假设二甲基富马酸（DMF），一种具有代谢作用的临床批准的抗炎药物，通过调节巨噬细胞和成纤维细胞代谢来改善 MI 后重塑。成年雄性 C57BL/6J 小鼠在 MI 后 3-7 天用 DMF（10mg/kg）治疗。DMF 在 MI 后 3 和 7 天减轻 LV 梗死和非梗死壁变薄，并在第 7 天减少 LV 扩张和肺充血。DMF 在第 7 天改善 LV 梗死胶原沉积、肌成纤维细胞激活和血管生成。DMF 还在 MI 后 3 天降低促炎细胞因子表达（Tnf），并降低从梗死心脏分离的巨噬细胞中的炎症标志物（Hif1a、Il1b）。在第 3 天从梗死心脏提取的成纤维细胞中，RNA-Seq 分析表明 DMF 促进了抗炎/修复表型。通过 Seahorse 分析，DMF 在第 3 天对巨噬细胞和成纤维细胞的糖酵解均无影响，但增强了巨噬细胞 OXPHOS，同时损害了成纤维细胞 OXPHOS。我们的结果表明，DMF 以不同的方式影响巨噬细胞和成纤维细胞的代谢，并促进抗炎/修复作用。总之，靶向梗死心脏中的细胞代谢可能是一种有前途的治疗策略。
