Niu Pei, Shindo Takayuki, Iwata Hiroshi, Iimuro Satoshi, Takeda Norifumi, Zhang Yuelan, Ebihara Aya, Suematsu Yoshihiro, Kangawa Kenji, Hirata Yasunobu, Nagai Ryozo
Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Circulation. 2004 Apr 13;109(14):1789-94. doi: 10.1161/01.CIR.0000118466.47982.CC. Epub 2004 Feb 16.
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.
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.
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.
肾上腺髓质素（AM）是一种新型血管舒张肽，被认为对心血管功能有重要影响。本研究的目的是使用AM基因敲除小鼠评估心血管系统中内源性AM的活性。
对AM基因无效突变的杂合子小鼠（AM+/-）及其野生型同窝小鼠进行主动脉缩窄或输注血管紧张素II（Ang II）。由此产生的心血管应激导致心脏重量/体重比增加、左心室壁厚度增加、血管周围纤维化，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的基因表达增加。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伤。在所有情况下，这些影响在AM+/-小鼠中更为明显。接受主动脉缩窄的成年小鼠心脏显示细胞外信号调节激酶（ERK）激活增强，用Ang II急性处理的新生小鼠心肌细胞也是如此。同样，这种影响在AM+/-小鼠中更为明显，AM+/-小鼠的心肌细胞大小、蛋白质合成和成纤维细胞增殖增加。在AM+/-心肌细胞中，蛋白激酶C抑制对ERK激活的抑制作用更大。此外，用重组AM处理心肌细胞可通过蛋白激酶A依赖性途径抑制Ang II诱导的ERK激活。
内源性AM通过蛋白激酶C和蛋白激酶A依赖性调节ERK激活，对应激诱导的心脏肥大发挥保护作用。因此，AM可能是治疗心血管疾病的一种有用的新工具。
