Protective effects of endogenous adrenomedullin on cardiac hypertrophy, fibrosis, and renal damage
Protective effects of endogenous adrenomedullin on cardiac hypertrophy, fibrosis, and renal damage
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DOI：
10.1161/01.cir.0000118466.47982.cc
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发表时间：
2004-04-13
期刊：
影响因子：
37.8
通讯作者：
Nagai, R
中科院分区：
文献类型：
--
作者：
Niu, P;Shindo, T;Nagai, R
背景-肾上腺髓质素（AM）是一种新的血管舒张肽，被认为对心血管功能有重要作用.本研究的目的是评估内源性AM在心血管系统中使用AM基因敲除小鼠的活动。方法和结果-小鼠杂合子的AM无效突变（AM +/-）和野生型同窝出生的人进行主动脉收缩或血管紧张素II（Ang II）输注。由此产生的心血管应激导致心脏重量/体重比、左心室壁厚度和血管周围纤维化的增加，以及编码血管紧张素原、ACE、转化生长因子-β、I型胶原、脑钠肽和c-fos的基因的表达。此外，还观察到以肌酐清除率降低伴肾小球硬化为特征的肾损害。在所有情况下，在AM +/-小鼠中的效果显著更明显。主动脉缩窄的成年小鼠心脏显示出细胞外信号调节激酶（ERK）激活增强，用Ang II急性治疗的新生儿心肌细胞也是如此。同样，这种作用在AM +/-小鼠中更为明显，其显示心肌细胞大小、蛋白质合成和成纤维细胞增殖增加。在AM +/-肌细胞中，ERK激活被蛋白激酶C抑制到更大程度。此外，治疗心肌细胞与重组AM抑制血管紧张素II诱导的ERK激活通过蛋白激酶A依赖pathway.Conclusions -内源性AM通过蛋白激酶C和蛋白激酶A依赖调节ERK激活对应激诱导的心肌肥大发挥保护作用。因此，AM可能是治疗心血管疾病的一种有用的新工具。
Background - Adrenomedullin (AM) is a novel vasodilating peptide thought to have important effects on cardiovascular function. The aim of this study was to assess the activity of endogenous AM in the cardiovascular system using AM knockout mice.Methods and Results - Mice heterozygous for an AM-null mutation (AM +/-) and their wild-type littermates were subjected to aortic constriction or angiotensin II (Ang II) infusion. The resultant cardiovascular stress led to increases in heart weight/body weight ratios, left ventricular wall thickness, and perivascular fibrosis, as well as expression of genes encoding angiotensinogen, ACE, transforming growth factor-beta, collagen type I, brain natriuretic peptide, and c-fos. In addition, renal damage characterized by decreased creatinine clearance with glomerular sclerosis was noted. In all cases, the effects were significantly more pronounced in AM +/- mice. Hearts from adult mice subjected to aortic constriction showed enhanced extracellular signal-regulated kinase (ERK) activation, as did cardiac myocytes from neonates treated acutely with Ang II. Again the effect was more pronounced in AM +/- mice, which showed increases in cardiac myocyte size, protein synthesis, and fibroblast proliferation. ERK activation was suppressed by protein kinase C inhibition to a greater degree in AM +/- myocytes. In addition, treatment of cardiac myocytes with recombinant AM suppressed Ang II - induced ERK activation via a protein kinase A - dependent pathway.Conclusions - Endogenous AM exerts a protective effect against stress-induced cardiac hypertrophy via protein kinase C and protein kinase A - dependent regulation of ERK activation. AM may thus represent a useful new tool for the treatment of cardiovascular disease.