Alteration of gene expression during progression of hypertension-induced cardiac dysfunction in rats
Alteration of gene expression during progression of hypertension-induced cardiac dysfunction in rats
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DOI：
10.1152/ajpheart.00289.2008
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发表时间：
2008-07-01
影响因子：
4.8
通讯作者：
Mochly-Rosen, Daria
中科院分区：
文献类型：
--
作者：
Koyanagi, Tomoyoshi;Wong, Lily Y.;Mochly-Rosen, Daria
高盐饮食诱导的达尔盐敏感大鼠在11周左右出现代偿性心脏肥大，在17周左右出现心功能障碍，在21周左右出现心功能障碍死亡。目前尚不清楚哪些分子标志区分代偿性肥厚和失代偿性心功能不全阶段。在这里，我们比较了代偿性肥厚期（11 周，n = 6）、心功能不全期（17 周，n = 6）以及年龄匹配的正常血压对照大鼠心脏组织中的基因表达。通过定量实时 PCR 测量了 93 个基因的信使 RNA 水平，这些基因是根据与心脏功能障碍的预测关联而选择的。在肥大期，心房钠尿肽（ANP；P = 0.0089）、脑钠尿肽（P = 0.0012）和内皮素-1前体（P = 0.028）3个基因的表达显着增加，而SOD2（P = 0.0148）、sarco（endo）质网等24个基因的表达下降Ca2+-ATPase 2a (P = 0.0002) 和兰尼碱受体 2 (P = 0.0319)。在随后的心功能不全阶段，与年龄匹配的对照组相比，诱导型一氧化氮合酶（NOS；P=0.0135）、血管紧张素I转换酶（P=0.0082）和IL-1β（P<0.0001）等另外20个基因的表达增加，而7个基因的表达减少。此外，与代偿性肥厚期相比，前内皮素原1、ANP、血管紧张素I转换酶、β(1)-肾上腺素能受体、SOD2和内皮NOS等22个基因的表达在心功能不全期发生显着变化。最后，主成分分析成功地将失代偿性心功能不全的动物与对照组以及代偿性肥大阶段的动物分开，这表明我们已经确定了该疾病每个阶段的分子标记。
Hypertension induced by high-salt diet in Dahl salt-sensitive rats leads to compensatory cardiac hypertrophy by similar to 11 wk, cardiac dysfunction at similar to 17 wk, and death from cardiac dysfunction at similar to 21 wk. It is unclear what molecular hallmarks distinguish the compensatory hypertrophy from the decompensated cardiac dysfunction phase. Here we compared the gene expression in rat cardiac tissue from the compensatory hypertrophic phase (11 wk, n = 6) with the cardiac dysfunction phase (17 wk, n = 6) and with age-matched normotensive controls. Messenger RNA levels of 93 genes, selected based on predicted association with cardiac dysfunction, were measured by quantitative real-time PCR. In the hypertrophic phase, the expression of three genes, atrial natriuretic peptide (ANP; P = 0.0089), brain natriuretic peptide (P = 0.0012), and endothelin-1 precursor (P = 0.028), significantly increased, whereas there was decreased expression of 24 other genes including SOD2 (P = 0.0148), sarco(endo) plasmic reticulum Ca2+-ATPase 2a (P = 0.0002), and ryanodine receptor 2 (P = 0.0319). In the subsequent heart cardiac dysfunction phase, the expression of an additional 20 genes including inducible nitric oxide synthase (NOS; P = 0.0135), angiotensin I-converting enzyme (P = 0.0082), and IL-1 beta (P < 0.0001) increased, whereas the expression of seven genes decreased compared with those of age-matched controls. Furthermore, the expression of 22 genes, including prepro-endothelin-1, ANP, angiotensin I-converting enzyme, beta(1)-adrenergic receptor, SOD2, and endothelial NOS, significantly changed in the cardiac dysfunction phase compared with the compensatory hypertrophic phase. Finally, principal component analysis successfully segregated animals with decompensatory cardiac dysfunction from controls, as well as from animals at the compensated hypertrophy phase, suggesting that we have identified molecular markers for each stage of the disease.