Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA.
Physiol Genomics. 2012 May 1;44(10):562-75. doi: 10.1152/physiolgenomics.00163.2011. Epub 2012 Mar 27.
MicroRNAs (miRs) are small, noncoding RNAs that are emerging as crucial regulators of cardiac remodeling in left ventricular hypertrophy (LVH) and failure (LVF). However, there are no data on their role in right ventricular hypertrophy (RVH) and failure (RVF). This is a critical question given that the RV is uniquely at risk in patients with congenital right-sided obstructive lesions and in those with systemic RVs. We have developed a murine model of RVH and RVF using pulmonary artery constriction (PAC). miR microarray analysis of RV from PAC vs. control demonstrates altered miR expression with gene targets associated with cardiomyocyte survival and growth during hypertrophy (miR 199a-3p) and reactivation of the fetal gene program during heart failure (miR-208b). The transition from hypertrophy to heart failure is characterized by apoptosis and fibrosis (miRs-34, 21, 1). Most are similar to LVH/LVF. However, there are several key differences between RV and LV: four miRs (34a, 28, 148a, and 93) were upregulated in RVH/RVF that are downregulated or unchanged in LVH/LVF. Furthermore, there is a corresponding downregulation of their putative target genes involving cell survival, proliferation, metabolism, extracellular matrix turnover, and impaired proteosomal function. The current study demonstrates, for the first time, alterations in miRs during the process of RV remodeling and the gene regulatory pathways leading to RVH and RVF. Many of these alterations are similar to those in the afterload-stressed LV. miRs differentially regulated between the RV and LV may contribute to the RVs increased susceptibility to heart failure.
微小 RNA（miRs）是一类新出现的小非编码 RNA，它们在左心室肥厚（LVH）和衰竭（LVF）中的心脏重构中起着至关重要的调节作用。然而，关于它们在右心室肥厚（RVH）和衰竭（RVF）中的作用，还没有数据。考虑到右心室在先天性右心阻塞性病变患者和全身性右心室患者中具有独特的风险，这是一个关键问题。我们使用肺动脉缩窄（PAC）建立了右心室肥厚和衰竭的小鼠模型。PAC 与对照 RV 的 miR 微阵列分析显示，miR 表达发生改变，与肥厚过程中的心肌细胞存活和生长相关的基因靶点（miR 199a-3p）和心力衰竭期间胎儿基因程序的再激活（miR-208b）有关。从肥厚到心力衰竭的转变以凋亡和纤维化（miRs-34、21、1）为特征。大多数与 LVH/LVF 相似。然而，RV 和 LV 之间存在几个关键差异：在 RVH/RVF 中上调的四个 miR（34a、28、148a 和 93）在 LVH/LVF 中下调或不变。此外，其假定的靶基因涉及细胞存活、增殖、代谢、细胞外基质周转和受损蛋白酶体功能的相应下调。本研究首次证明了 RV 重构过程中 miR 的变化以及导致 RVH 和 RVF 的基因调控途径。这些改变中的许多与负荷后 LV 的改变相似。RV 和 LV 之间差异调节的 miR 可能导致 RV 对心力衰竭的易感性增加。
