Department of Pediatrics, University of California , San Francisco, California.
Department of Surgery, University of California , Davis, California.
Am J Physiol Heart Circ Physiol. 2018 Oct 1;315(4):H847-H854. doi: 10.1152/ajpheart.00057.2018. Epub 2018 Jun 15.
The right ventricular (RV) response to pulmonary arterial hypertension (PAH) is heterogeneous. Most patients have maladaptive changes with RV dilation and RV failure, whereas some, especially patients with PAH secondary to congenital heart disease, have an adaptive response with hypertrophy and preserved systolic function. Mechanisms for RV adaptation to PAH are unknown, despite RV function being a primary determinant of mortality. In our congenital heart disease ovine model with fetally implanted aortopulmonary shunt (shunt lambs), we previously demonstrated an adaptive physiological RV response to increased afterload with hypertrophy. In the present study, we examined small noncoding microRNA (miRNA) expression in shunt RV and characterized downstream effects of a key miRNA. RV tissue was harvested from 4-wk-old shunt and control lambs ( n = 5), and miRNA, mRNA, and protein were quantitated. We found differential expression of 40 cardiovascular-specific miRNAs in shunt RV. Interestingly, this miRNA signature is distinct from models of RV failure, suggesting that miRNAs might contribute to adaptive RV hypertrophy. Among RV miRNAs, miR-199b was decreased in the RV with eventual downregulation of nuclear factor of activated T cells/calcineurin signaling. Furthermore, antifibrotic miR-29a was increased in the shunt RV with a reduction of the miR-29 targets collagen type A1 and type 3A1 and decreased fibrosis. Thus, we conclude that the miRNA signature specific to shunt lambs is distinct from RV failure and drives gene expression required for adaptive RV hypertrophy. We propose that the adaptive RV miRNA signature may serve as a prognostic and therapeutic tool in patients with PAH to attenuate or prevent progression of RV failure and premature death. NEW & NOTEWORTHY This study describes a novel microRNA signature of adaptive right ventricular hypertrophy, with particular attention to miR-199b and miR-29a.
右心室（RV）对肺动脉高压（PAH）的反应是异质的。大多数患者的 RV 扩张和 RV 衰竭表现为适应性变化，而有些患者，特别是继发于先天性心脏病的 PAH 患者，表现为肥厚和收缩功能保留的适应性反应。尽管 RV 功能是死亡率的主要决定因素，但 RV 适应 PAH 的机制尚不清楚。在我们以前的研究中，我们使用具有胎儿植入式体肺分流（分流羊）的先天性心脏病绵羊模型，证明了 RV 对后负荷增加的适应性生理反应是通过肥厚来实现的。在本研究中，我们检查了分流 RV 中的小非编码 microRNA（miRNA）表达，并对关键 miRNA 的下游效应进行了表征。从 4 周龄分流和对照羊的 RV 组织中提取了 miRNA、mRNA 和蛋白质，并进行了定量分析。我们发现分流 RV 中有 40 种心血管特异性 miRNA 表达差异。有趣的是，这种 miRNA 特征与 RV 衰竭模型不同，这表明 miRNA 可能有助于适应性 RV 肥厚。在 RV miRNA 中，miR-199b 在 RV 中减少，最终导致激活 T 细胞核因子/钙调神经磷酸酶信号下调。此外，抗纤维化的 miR-29a 在分流 RV 中增加，导致 miR-29 的靶标胶原 A1 型和 3A1 型减少，纤维化减少。因此，我们得出结论，分流羊的 miRNA 特征与 RV 衰竭不同，它驱动了适应性 RV 肥厚所需的基因表达。我们提出，适应性 RV miRNA 特征可作为 PAH 患者的预后和治疗工具，以减轻或预防 RV 衰竭和过早死亡的进展。
