Division of Cardiology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.
Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
JCI Insight. 2019 Apr 25;5(11):122929. doi: 10.1172/jci.insight.122929.
Right ventricular dysfunction is highly prevalent across cardiopulmonary diseases and independently predicts death in both heart failure (HF) and pulmonary hypertension (PH). Progression towards right ventricular failure (RVF) can occur in spite of optimal medical treatment of HF or PH, highlighting current insufficient understanding of RVF molecular pathophysiology. To identify molecular mechanisms that may distinctly underlie RVF, we investigated the cardiac ventricular transcriptome of advanced HF patients, with and without RVF. Using an integrated systems genomic and functional biology approach, we identified an RVF-specific gene module, for which WIPI1 served as a hub and HSPB6 and MAP4 as drivers, and confirmed the ventricular specificity of Wipi1, Hspb6, and Map4 transcriptional changes in adult murine models of pressure overload induced RV- versus LV- failure. We uncovered a shift towards non-canonical autophagy in the failing RV that correlated with RV-specific Wipi1 upregulation. In vitro siRNA silencing of Wipi1 in neonatal rat ventricular myocytes limited non-canonical autophagy and blunted aldosterone-induced mitochondrial superoxide levels. Our findings suggest that Wipi1 regulates mitochondrial oxidative signaling and non-canonical autophagy in cardiac myocytes. Together with our human transcriptomic analysis and corroborating studies in an RVF mouse model, these data render Wipi1 a potential target for RV-directed HF therapy.
右心室功能障碍在心肺疾病中普遍存在，并且独立预测心力衰竭 (HF) 和肺动脉高压 (PH) 患者的死亡。尽管 HF 或 PH 得到了最佳的药物治疗，但仍可能会出现右心室衰竭 (RVF)，这突显了目前对 RVF 分子病理生理学的理解不足。为了确定可能明显导致 RVF 的分子机制，我们研究了有和没有 RVF 的晚期 HF 患者的心脏心室转录组。我们使用综合系统基因组和功能生物学方法，确定了一个 RVF 特异性基因模块，其中 WIPI1 作为枢纽，HSPB6 和 MAP4 作为驱动因素，并且在压力超负荷诱导的 RV 与 LV 衰竭的成年鼠模型中证实了 Wipi1、Hspb6 和 Map4 转录变化的心室特异性。我们发现衰竭的 RV 中出现了非典型自噬的转变，这与 RV 特异性 Wipi1 上调有关。在体外使用 siRNA 沉默新生大鼠心室肌细胞中的 Wipi1 可限制非典型自噬并减轻醛固酮诱导的线粒体超氧化物水平。我们的研究结果表明，Wipi1 调节心肌细胞中线粒体氧化信号和非典型自噬。这些数据与我们的人类转录组分析和 RVF 小鼠模型的佐证研究一起，表明 Wipi1 可能成为 RV 导向的 HF 治疗的潜在靶点。
