Investigation of the treatment of silent heart failure by controllingof multi-organ network and epigenic modulation

Midkine是一种肝素结合生长因子，具有多种功能，如细胞生长、细胞存活、炎症细胞迁移等。我们之前报道过血清midkine水平与心力衰竭患者的不良心脏事件独立相关。本研究旨在探讨midkine在心力衰竭发病机制中的作用。Midkine表达水平主要在主动脉横缩术（TAC）后升高。我们利用α-肌球蛋白重链启动子构建了心肌特异性过表达midkine（MK-Tg）的转基因小鼠。TAC手术后，MK-Tg小鼠的细胞外信号调节激酶（ERK） 1/2和AKT的磷酸化水平以及胎儿基因在心脏中的表达水平明显高于WT小鼠。TAC术后MK-Tg小鼠左室重量与体重之比、左室舒张末期尺寸均显著增加，左室缩短分数、左室发育压力最大值和最小值均显著低于wt小鼠。MK-Tg小鼠间质纤维化程度和纤维化基因表达明显高于WT小鼠。与这些结果一致，Kaplan-Meier分析显示MK-Tg小鼠的存活率明显低于WT小鼠。我们得出结论，心肌中mk的过表达在压力过载引起的心肌肥大和重构中起关键作用。

Midkine is a heparin-binding growth factor having various functions such as cell growth,cell survival, and migration of inflammatory cells. We have previously reported thatserum midkine levels are independently associated with adverse cardiac events in patientswith heart failure. The aim of this study was to examine the role of midkine on thepathogenesis of the heart failure.Midkine expression levels were mainly increased after transverse aortic constriction (TAC)surgery. We generated transgenic mice with cardiac specific overexpression of midkine(MK-Tg) using α-myosin heavy chain promoter. After TAC operation, phosphorylation ofextracellular signal-regulated kinase (ERK) 1/2 and AKT, and the expression levels of fetalgene in the heart were significantly increased in MK-Tg mice than in WT mice. The ratioof left ventricular weight to body weight and left ventricular end-diastolic dimension weresignificantly increased, and fractional shortening and maximum and minimum of leftventricular developed pressure were significantly decreased in MK-Tg mice than in WTmice after TAC operation. The degree of interstitial fibrosis and profibrotic geneexpressions were significantly higher in MK-Tg mice than in WT mice. Consistent withthese results, Kaplan-Meier analysis revealed that the survival rate in MK-Tg mice wassignificantly lower compared with WT mice. We concluded that cardiac overexpression ofMK plays a critical role in pressure overload induced cardiac hypertrophy and remodeling.