Mao Yajing, Koga Jun-Ichiro, Tokutome Masaki, Matoba Tetsuya, Ikeda Gentaro, Nakano Kaku, Egashira Kensuke
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University.
Department of Cardiovascular Research, Development, and Translational Medicine, Center for Disruptive Cardiovascular Medicine, Kyushu University.
Int Heart J. 2017 Aug 3;58(4):615-623. doi: 10.1536/ihj.16-457. Epub 2017 Jul 13.
Left ventricular (LV) remodeling after myocardial infarction (MI) causes heart failure. Although medical therapies including angiotensin converting enzyme inhibitors show inhibitory effects on post-infarct LV remodeling, the prognosis of patients with post-infarct heart failure is still poor. Accumulating evidence suggests that an inflammatory response is implicated in the process of post-infarct LV remodeling. Therefore, we hypothesized that anti-inflammatory therapy by nanoparticle-mediated monocyte/macrophage-targeting delivery of pitavastatin may protect the heart from post-infarct LV remodeling.Male C57BL/6 mice were subjected to permanent coronary ligation and pitavastatin-incorporating nanoparticles (Pitavastatin-NPs) were intravenously injected for 3 to 5 consecutive days. Pitavastatin-NPs were delivered to CD11b monocytes/macrophages, but not to cardiomyocytes. Treatment with Pitavastatin-NPs after establishment of MI attenuated post-infarct LV remodeling accompanied by a reduction of monocytes/macrophages in the heart, whereas pitavastatin solution treatment did not. Pitavastatin-NPs inhibited mobilization of monocytes from the spleen after MI. In mice after splenectomy, Pitavastatin-NPs still decreased the number of monocytes/macrophages in the infarcted heart and inhibited post-infarct LV remodeling.Nanoparticle-mediated delivery of pitavastatin to monocytes/macrophages may be a novel therapeutic strategy to protect the heart from post-infarct LV remodeling. Inhibition of monocyte mobilization from the bone marrow is one of the major mechanisms by which Pitavastatin-NPs attenuated post-infarct LV remodeling.
心肌梗死后左心室重构会导致心力衰竭。尽管包括血管紧张素转换酶抑制剂在内的药物治疗对梗死后左心室重构具有抑制作用，但梗死后心力衰竭患者的预后仍然很差。越来越多的证据表明，炎症反应与梗死后左心室重构过程有关。因此，我们推测通过纳米颗粒介导的匹伐他汀靶向单核细胞/巨噬细胞递送进行抗炎治疗可能保护心脏免受梗死后左心室重构的影响。雄性C57BL/6小鼠接受永久性冠状动脉结扎，并连续3至5天静脉注射含匹伐他汀的纳米颗粒（匹伐他汀纳米颗粒）。匹伐他汀纳米颗粒被递送至CD11b单核细胞/巨噬细胞，但未递送至心肌细胞。心肌梗死后用匹伐他汀纳米颗粒治疗可减轻梗死后左心室重构，同时心脏中的单核细胞/巨噬细胞减少，而匹伐他汀溶液治疗则没有这种效果。匹伐他汀纳米颗粒抑制心肌梗死后脾脏中单核细胞的动员。在脾切除术后的小鼠中，匹伐他汀纳米颗粒仍然减少梗死心脏中单核细胞/巨噬细胞的数量并抑制梗死后左心室重构。纳米颗粒介导的匹伐他汀向单核细胞/巨噬细胞递送可能是一种保护心脏免受梗死后左心室重构影响的新型治疗策略。抑制骨髓中单核细胞的动员是匹伐他汀纳米颗粒减轻梗死后左心室重构的主要机制之一。
