Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Am J Physiol Heart Circ Physiol. 2013 May 15;304(10):H1314-27. doi: 10.1152/ajpheart.00776.2012. Epub 2013 Mar 15.
Pulmonary insufficiency (PI) is a common long-term sequel after repair of tetralogy of Fallot, causing progressive right ventricular (RV) dilation and failure. We describe the physiologic and molecular characteristics of the first murine model of RV volume overload. PI was created by entrapping the pulmonary valve leaflets with sutures. Imaging, catheterization, and exercise testing were performed at 1, 3, and 6 mo and compared with sham controls. RNA from the RV free wall was hybridized to Agilent whole genome oligonucleotide microarrays. Volume overload resulted in RV enlargement, decreased RV outflow tract shortening fraction at 1 mo followed by normalization at 3 and 6 mo (39 ± 2, 44 ± 2, and 41 ± 2 vs. 46 ± 3% in sham), early reversal of early and late diastolic filling velocities (E/A ratio) followed by pseudonormalization (0.87 ± 0.08, 0.82 ± 0.08, and 0.96 ± 0.08 vs. 1.04 ± 0.03; P < 0.05), elevated end-diastolic pressure (7.6 ± 0.7, 6.9 ± 0.8, and 7 ± 0.5 vs. 2.7 ± 0.2 mmHg; P < 0.05), and decreased exercise duration (26 ± 0.4, 26 ± 1, and 22 ± 1.3 vs. 30 ± 1.1 min; P < 0.05). Subendocardial RV fibrosis was evident by 1 mo. At 1 mo, 372 genes were significantly downregulated. Mitochondrial pathways and G protein-coupled receptor signaling were the most represented categories. At 3 mo, 434 genes were upregulated and 307 downregulated. While many of the same pathways continued to be downregulated, TNF-α, transforming growth factor-β(1) (TGF-β(1)), p53-signaling, and extracellular matrix (ECM) remodeling transitioned from down- to upregulated. We describe a novel murine model of chronic RV volume overload recapitulating aspects of the clinical disease with gene expression changes suggesting early mitochondrial bioenergetic dysfunction, enhanced TGF-β signaling, ECM remodeling, and apoptosis.
肺功能不全（PI）是法洛四联症修复后的一种常见的长期后遗症，导致右心室（RV）进行性扩张和衰竭。我们描述了第一个 RV 容量超负荷的小鼠模型的生理和分子特征。通过缝线将肺动脉瓣叶困住来创建 PI。在 1、3 和 6 个月时进行成像、心导管检查和运动测试，并与假手术对照进行比较。将 RV 游离壁的 RNA 与安捷伦全基因组寡核苷酸微阵列杂交。RV 增大导致容量超负荷，1 个月时 RV 流出道缩短分数降低，随后在 3 和 6 个月时恢复正常（39 ± 2、44 ± 2 和 41 ± 2 与假手术组的 46 ± 3%相比），早期舒张早期和晚期充盈速度（E/A 比值）逆转，随后假性正常化（0.87 ± 0.08、0.82 ± 0.08 和 0.96 ± 0.08 与 1.04 ± 0.03 相比；P < 0.05），舒张末期压力升高（7.6 ± 0.7、6.9 ± 0.8 和 7 ± 0.5 与 2.7 ± 0.2 mmHg 相比；P < 0.05），运动时间缩短（26 ± 0.4、26 ± 1 和 22 ± 1.3 与 30 ± 1.1 min 相比；P < 0.05）。1 个月时可见 RV 心内膜下纤维化。1 个月时，有 372 个基因显著下调。线粒体途径和 G 蛋白偶联受体信号转导是最具代表性的类别。3 个月时，有 434 个基因上调，307 个基因下调。虽然许多相同的途径继续下调，但 TNF-α、转化生长因子-β1（TGF-β1）、p53 信号和细胞外基质（ECM）重塑从下调转为上调。我们描述了一种新的慢性 RV 容量超负荷的小鼠模型，该模型再现了临床疾病的某些方面，基因表达的变化表明早期线粒体生物能功能障碍、增强的 TGF-β 信号、ECM 重塑和细胞凋亡。
