Wei Xuan, Wu Bing, Zhao Jing, Zeng Zhi, Xuan Wanling, Cao Shiping, Huang Xiaobo, Asakura Masanori, Xu Dingli, Bin Jianping, Kitakaze Masafumi, Liao Yulin
From Sate Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China (X.W., B.W., J.Z., Z.Z., W.X., S.C., X.H., D.X., J.B., M.K., Y.L.); and Cardiovascular Division of the Department of Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan (M.A., M.K.).
Circulation. 2015 Apr 28;131(17):1506-17; discussion 1517. doi: 10.1161/CIRCULATIONAHA.114.013789. Epub 2015 Mar 27.
Transient preceding brief ischemia provides potent cardioprotection against subsequent long ischemia, termed ischemic preconditioning. Here, we hypothesized that transient short-term hypertrophic stimulation would induce the expression of hypertrophy regression genes and render the heart resistant to subsequent hypertrophic stress, and slow the progression to heart failure, as well.
Cardiomyocyte hypertrophy was induced in mice by either transverse aortic constriction or an infusion of phenylephrine, and in neonatal rat ventricular cardiomyocytes by norepinephrine exposures. In the preconditioning groups, hypertrophic stimulation was provided for 1 to 7 days and then withdrawn for several days by either aortic debanding or discontinuing phenylephrine or norepinephrine treatment, followed by subsequent reexposure to the hypertrophic stimulus for the same period as in the control group. One or 6 weeks after transverse aortic constriction, the heart weight/body weight ratio was lower in the preconditioning group than in the control group, whereas the lung weight/body weight ratio was significantly decreased 6 weeks after transverse aortic constriction. Similar results were obtained in mice receiving phenylephrine infusion and neonatal rat ventricular cardiomyocytes stimulated with norepinephrine. Both mRNA and protein expression of S100A8 and S100A9 showed significant upregulation after the removal of hypertrophic stimulation and persisted for 6 weeks in response to reimposition of transverse aortic constriction. The treatment with recombinant S100A8/A9 inhibited norepinephrine-induced myocyte hypertrophy and reduced the expression of calcineurin and NFATc3, but the silencing of S100A8/A9 prevented such changes.
Preconditioning with prohypertrophic factors exerts an antihypertrophic effect and slows the progression of heart failure, indicating the existence of the phenomenon for hypertrophic preconditioning.
短暂的缺血预处理可对随后的长时间缺血提供强大的心脏保护作用，即缺血预处理。在此，我们假设短暂的短期肥厚刺激会诱导肥厚消退基因的表达，使心脏对随后的肥厚应激产生抗性，并减缓心力衰竭的进展。
通过横断主动脉缩窄或注射去氧肾上腺素在小鼠中诱导心肌细胞肥大，通过去甲肾上腺素处理在新生大鼠心室心肌细胞中诱导肥大。在预处理组中，给予1至7天的肥厚刺激，然后通过主动脉松绑或停止去氧肾上腺素或去甲肾上腺素处理撤药数天，随后再次暴露于肥厚刺激，持续时间与对照组相同。横断主动脉缩窄1或6周后，预处理组的心脏重量/体重比低于对照组，而横断主动脉缩窄6周后肺重量/体重比显著降低。在用去氧肾上腺素注射的小鼠和用去甲肾上腺素刺激的新生大鼠心室心肌细胞中也获得了类似结果。去除肥厚刺激后，S100A8和S100A9的mRNA和蛋白表达均显著上调，并在再次施加横断主动脉缩窄后持续6周。重组S100A8/A9处理可抑制去甲肾上腺素诱导的心肌细胞肥大，并降低钙调神经磷酸酶和NFATc3的表达，但沉默S100A8/A9可阻止这些变化。
用促肥厚因子进行预处理可发挥抗肥厚作用并减缓心力衰竭的进展，表明存在肥厚预处理现象。
