Microarray analysis reveals pivotal divergent mRNA expression profiles early in the development of either compensated ventricular hypertrophy or heart failure
Microarray analysis reveals pivotal divergent mRNA expression profiles early in the development of either compensated ventricular hypertrophy or heart failure
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DOI：
10.1152/physiolgenomics.00185.2004
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发表时间：
2005-05-11
影响因子：
4.6
通讯作者：
Simonides, WS
中科院分区：
文献类型：
--
作者：
Buermans, HPJ;Redout, EM;Simonides, WS
肺动脉高压导致的心肌右心室（RV）肥大旨在使心室壁应力正常化。根据压力超负荷的程度，RV肥大可能进展到收缩功能受损和心力衰竭的状态，但这在心室重塑的早期阶段无法识别。我们测试了在最终发展为代偿性或失代偿性肥大表型之前，心室之间是否存在基因表达谱的关键差异。这两种表型选择性诱导Wistar大鼠通过单次皮下注射低或高剂量的吡咯里西啶生物碱野百合碱（MCT）。斑点寡核苷酸微阵列用于研究MCT注射后2周，对照大鼠和最终发生代偿性或失代偿性肥大的大鼠之间的压力依赖性心脏基因表达谱。显著调节基因的聚类揭示了每组的特异性表达谱，尽管两者的肥大程度仍然相似。注定进展到衰竭的心室显示促凋亡途径的激活，特别是与线粒体相关的，而发展代偿性肥大的组显示通过MAPK磷酸酶-1的上调通过p38-MAPK阻断促死亡效应物信号传导。总之，我们表明，在早期的时间点，基因表达的关键差异存在于心室之间，最终将发展为代偿或失代偿表型，这取决于压力超负荷的程度。这些数据揭示了可能为临床结果的早期预测以及早期干预的潜在靶点提供标记的基因。
Myocardial right ventricular (RV) hypertrophy due to pulmonary hypertension is aimed at normalizing ventricular wall stress. Depending on the degree of pressure overload, RV hypertrophy may progress to a state of impaired contractile function and heart failure, but this cannot be discerned during the early stages of ventricular remodeling. We tested whether critical differences in gene expression profiles exist between ventricles before the ultimate development of either a compensated or decompensated hypertrophic phenotype. Both phenotypes were selectively induced in Wistar rats by a single subcutaneous injection of either a low or a high dose of the pyrrolizidine alkaloid monocrotaline (MCT). Spotted oligonucleotide microarrays were used to investigate pressure-dependent cardiac gene expression profiles at 2 wk after the MCT injections, between control rats and rats that would ultimately develop either compensated or decompensated hypertrophy. Clustering of significantly regulated genes revealed specific expression profiles for each group, although the degree of hypertrophy was still similar in both. The ventricles destined to progress to failure showed activation of pro-apoptotic pathways, particularly related to mitochondria, whereas the group developing compensated hypertrophy showed blocked pro-death effector signaling via p38-MAPK, through upregulation of MAPK phosphatase-1. In summary, we show that, already at an early time point, pivotal differences in gene expression exist between ventricles that will ultimately develop either a compensated or a decompensated phenotype, depending on the degree of pressure overload. These data reveal genes that may provide markers for the early prediction of clinical outcome as well as potential targets for early intervention.