Midkine plays a protective role against cardiac ischemia/reperfusion injury through a reduction of apoptotic reaction
Midkine plays a protective role against cardiac ischemia/reperfusion injury through a reduction of apoptotic reaction
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DOI：
10.1161/circulationaha.106.632273
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发表时间：
2006-10-17
期刊：
影响因子：
37.8
通讯作者：
Kodama, Itsuo
中科院分区：
文献类型：
--
作者：
Horiba, Mitsuru;Kadomatsu, Kenji;Kodama, Itsuo
中期因子（MK）是一种肝素结合生长因子，参与多种生物学现象，如神经存活、癌发生和组织修复。MK对心肌缺血/再灌注（I/R）损伤具有保护作用，因为MK对培养的神经元和肿瘤细胞具有细胞保护作用。我们研究了这一假设在小鼠与基因MK deletion.Methods和结果-心肌损伤后，I/R是由冠状动脉短暂闭塞。在野生型（Mdk（+/+））小鼠中，MK表达在I/R后在梗塞周围区域增加。MK缺陷（Mdk（-/-））小鼠I/R后24小时的肿瘤大小/危险区域大于Mdk（+/+）小鼠（55.4 +/- 9.1%对32.1 +/-5.3%，P < 0.05）。Mdk（-/-）小鼠梗死周围区末端dUTP缺口末端标记阳性的心肌细胞群体高于Mdk（+/+）小鼠（6.8 +/- 0.9%对3.2 +/-0.6%，P < 0.05）。Mdk（-/-）小鼠I/R后24小时左室短轴缩短率显著低于Mdk（+/+）小鼠（34.3 ± 4.4% vs50.8 ± 2.1%，P < 0.05）。Mdk（-/-）小鼠在I/R时左心室补充MK蛋白导致梗死面积减小。应用外源性MK培养的心肌细胞导致Bcl-2的表达增加，减少凋亡缺氧/reoxygenation.Conclusions -这些结果表明，MK对I/R损伤起保护作用，最有可能通过预防凋亡反应。MK是治疗缺血性心脏病的一个潜在的重要新分子靶点。
Background - Midkine (MK) is a heparin-binding growth factor involved in diverse biological phenomena, eg, neural survival, carcinogenesis, and tissue repair. MK could have a protective action against ischemia/reperfusion (I/R) injury in the heart, because MK was shown to have cytoprotective activity in cultured neurons and tumor cells. We investigated this hypothesis in mice with and without genetic MK deletion.Methods and Results - Myocardial injury after I/R was produced by transient occlusion of coronary arteries. In wild-type (Mdk(+/+)) mice, MK expression was increased after I/R in the periinfarct area. Infarct size/area at risk 24 hours after I/R in MK-deficient (Mdk(-/-)) mice was larger than in Mdk(+/+) mice (55.4 +/- 9.1% versus 32.1 +/- 5.3%, P < 0.05). Terminal dUTP nick end-labeling-positive myocyte population in the periinfarct area in Mdk(-/-) mice was higher than in Mdk(+/+) mice (6.8 +/- 0.9% versus 3.2 +/- 0.6%, P < 0.05). Left ventricular fractional shortening 24 hours after I/R in Mdk(-/-) mice was significantly less than that in Mdk(+/+) mice (34.3 +/- 4.4% versus 50.8 +/- 2.1%, P < 0.05). Supplemental application of MK protein to left ventricle of Mdk(-/-) mice at the time of I/R resulted in reduction of the infarct size. Application of exogenous MK to cultured cardiomyocytes resulted in increased Bcl-2 expression and decreased apoptosis after hypoxia/reoxygenation.Conclusions - These results suggest that MK plays a protective role against I/R injury, most likely through a prevention of apoptotic reaction. MK is a potentially important new molecular target for treatment of ischemic heart disease.