Therapeutic effect of midkine on cardiac remodeling in infarcted rat hearts
Therapeutic effect of midkine on cardiac remodeling in infarcted rat hearts
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DOI：
10.1016/j.athoracsur.2007.06.002
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发表时间：
2008-02-01
影响因子：
4.6
通讯作者：
Sawa, Yoshiki
中科院分区：
文献类型：
--
作者：
Fukui, Shinya;Kitagawa-Sakakida, Satoru;Sawa, Yoshiki
背景。Midkine在发育中的胎儿和缺血应激的成人器官中表达，但其在缺血器官中的生理作用尚不清楚。研究了midkine对心肌梗死后缺血心肌重构的影响。心肌梗死后2周，采用实时聚合酶链反应法检测内源性midkine基因在大鼠心脏中的表达谱。在心肌梗死后2周注射重组midkine，用超声心动图监测心功能。6周后，取心脏，用组织学方法测定梗死面积、活组织面积及心肌细胞肥大程度。midkine基因在梗死心肌中强烈上调，但这种上调持续不到2周。midkine治疗显著且剂量依赖性地减轻了心脏重构。midkine治疗还增加了梗死区域的胶原积累，促进了血管生成，心肌梗死后的活肌面积呈剂量依赖性增加。尽管活肌面积增加，但midkine处理过的心脏心肌细胞肥大明显少于药物处理过的心脏，这表明midkine通过血管生成阻止了慢性缺血细胞的死亡和脱落。本研究结果表明，midkine可以减轻心肌梗死后的心脏重构，并提示midkine对亚急性心肌梗死具有治疗潜力。
Background. 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.Methods. 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.Results. 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.Conclusions. Our results indicate midkine can attenuate cardiac remodeling after myocardial infarction, and suggest midkine has therapeutic potential for subacute myocardial infarction.