Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Huro-cho, Chikusa-ku, Nagoya 464-8601, Japan.
Cardiovasc Res. 2010 Apr 1;86(1):113-21. doi: 10.1093/cvr/cvp386. Epub 2009 Dec 7.
We have previously reported that therapy with midkine (MK) has a protective effect in mouse models of myocardial infarction (MI) and ischemia/reperfusion. The underlying mechanism was proved to be anti-apoptosis and prevention of left ventricular (LV) remodelling following angiogenesis. Here we investigated the effects of overexpression of MK by adenoviral gene transfer on cardiac function and remodelling in an experimental rat MI model.
MI was created in male Wistar rats. Adenoviral vectors encoding mouse MK (AdMK) or beta-galactosidase (AdLacZ; as controls) were injected in myocardium at the onset of MI. One week after injection, in vivo adenoviral gene expression was assessed by western blot and histological analysis. After echocardiographic analysis at 4 weeks and haemodynamic analysis at 6 weeks after MI, AdMK animals had better cardiac function compared with AdLacZ animals. Heart weight (HW) and relative HW of AdMK animals were not different from sham-operated animals after 6 weeks, pointing to a very potent effect in the prevention of ischemic cardiomyopathy. In histological studies at 6 weeks after MI, AdMK animals had less fibrosis in the non-infarcted myocardium and higher vascular density in the border-zone area compared with AdLacZ animals. AdMK animals had strongly upregulated levels of phosphorylated extracellular signal-regulated kinase, Akt, PI 3-kinase, and Bcl-2, whereas the level of Bax was downregulated compared with AdLacZ animals.
Overexpression of MK prevents LV remodelling and ameliorates LV dysfunction by anti-apoptotic and pro-angiogenic effects. MK gene transfer may provide a new therapeutic modality in ischemic cardiomyopathy and ischemic heart failure.
我们之前曾报道过，中期因子（MK）治疗对心肌梗死（MI）和缺血/再灌注的小鼠模型具有保护作用。其潜在机制被证明是抗细胞凋亡和促进血管生成后防止左心室（LV）重构。在此，我们研究了通过腺病毒基因转移过表达 MK 对实验性大鼠 MI 模型心脏功能和重构的影响。
雄性 Wistar 大鼠创建 MI。在 MI 发生时，将编码小鼠 MK（AdMK）或β-半乳糖苷酶（AdLacZ；作为对照）的腺病毒载体注射到心肌中。注射后 1 周，通过 Western blot 和组织学分析评估体内腺病毒基因表达。在 MI 后 4 周进行超声心动图分析和 6 周进行血流动力学分析后，AdMK 动物的心脏功能优于 AdLacZ 动物。6 周后，AdMK 动物的心脏重量（HW）和相对 HW 与假手术动物无差异，表明其对缺血性心肌病具有非常有效的预防作用。在 MI 后 6 周的组织学研究中，AdMK 动物的非梗死心肌纤维化程度较低，边界区的血管密度较高。与 AdLacZ 动物相比，AdMK 动物的磷酸化细胞外信号调节激酶（ERK）、Akt、PI3-激酶和 Bcl-2 水平上调，而 Bax 水平下调。
MK 的过表达通过抗细胞凋亡和促血管生成作用防止 LV 重构并改善 LV 功能障碍。MK 基因转移可能为缺血性心肌病和缺血性心力衰竭提供新的治疗方法。
