Fukui Shinya, Kitagawa-Sakakida Satoru, Kawamata Sin, Matsumiya Goro, Kawaguchi Naomasa, Matsuura Nariaki, Sawa Yoshiki
Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Ann Thorac Surg. 2008 Feb;85(2):562-70. doi: 10.1016/j.athoracsur.2007.06.002.
Midkine is expressed in the developing fetus and in adult organs stressed by ischemia, but its physiologic role in ischemic organs is poorly understood. Here we investigated the effect of midkine on cardiac remodeling after ischemia caused by myocardial infarction.
The expression pattern of the endogenous midkine gene in rat heart was evaluated by real-time polymerase chain reaction for 2 weeks after myocardial infarction. To investigate its effect, recombinant midkine was injected into hearts 2 weeks after myocardial infarction, and cardiac functions were monitored by echocardiography. Six weeks later, the hearts were removed, and the areas of infarcted and viable tissue and the extent of cardiomyocyte hypertrophy were determined histologically.
The midkine gene was strongly upregulated in the infarcted myocardium, but this upregulation lasted less than 2 weeks. Cardiac remodeling was significantly and dose-dependently attenuated by midkine treatment. The midkine treatment also increased collagen accumulation and facilitated angiogenesis in the infarcted area, and the viable muscle area after myocardial infarction dose-dependently increased. Despite this increase of viable muscle area, the midkine-treated hearts showed significantly less cardiomyocyte hypertrophy than vehicle-treated hearts, suggesting midkine had prevented chronically ischemic cells from dying and dropping out by angiogenesis.
Our results indicate midkine can attenuate cardiac remodeling after myocardial infarction, and suggest midkine has therapeutic potential for subacute myocardial infarction.
中期因子在发育中的胎儿以及因缺血而应激的成体器官中表达，但其在缺血器官中的生理作用仍知之甚少。在此，我们研究了中期因子对心肌梗死后心肌缺血所致心脏重塑的影响。
通过实时聚合酶链反应评估大鼠心脏内源性中期因子基因在心肌梗死后2周内的表达模式。为研究其作用，在心肌梗死后2周将重组中期因子注入心脏，并通过超声心动图监测心脏功能。6周后，取出心脏，通过组织学方法确定梗死和存活组织的面积以及心肌细胞肥大的程度。
中期因子基因在梗死心肌中强烈上调，但这种上调持续时间不到2周。中期因子治疗可显著且剂量依赖性地减轻心脏重塑。中期因子治疗还增加了梗死区域的胶原积累并促进了血管生成，心肌梗死后存活肌肉面积呈剂量依赖性增加。尽管存活肌肉面积增加，但中期因子治疗的心脏与载体治疗的心脏相比，心肌细胞肥大明显减轻，这表明中期因子可通过血管生成防止长期缺血细胞死亡和脱落。
我们的结果表明，中期因子可减轻心肌梗死后的心脏重塑，并提示中期因子对亚急性心肌梗死具有治疗潜力。
