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

中期因子是肝素结合生长因子，具有多种功能，例如细胞生长、细胞存活和炎性细胞的迁移。我们以前曾报道，血清中期因子水平与心力衰竭患者的不良心脏事件独立相关。本研究的目的是探讨中期因子在心力衰竭发病机制中的作用，中期因子的表达水平主要在横主动脉缩窄术（TAC）后增加。我们使用α-肌球蛋白重链启动子产生了心脏特异性过表达中期因子（MK-Tg）的转基因小鼠。TAC手术后，MK-Tg小鼠心脏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的表达水平均显著高于WT小鼠。TAC术后MK-Tg小鼠左室重量/体重比、左室舒张末期内径均显著增加，左室短轴缩短率、左室最大和最小发展压均显著降低。MK-Tg小鼠的间质纤维化程度和促纤维化基因表达显著高于WT小鼠。Kaplan-Meier分析结果表明，MK-Tg小鼠的存活率明显低于WT小鼠。我们的结论是，心肌MK的过度表达在压力超负荷诱导的心肌肥厚和重塑中起着关键作用。

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.