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, Columbia University researchers used RNA sequencing to investigate the cardiac ventricular transcriptome of advanced HF patients, with and without RVF. Using an integrated systems genomic and functional biology approach, they 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. The researchers 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. These findings suggest that Wipi1 regulates mitochondrial oxidative signaling and non-canonical autophagy in cardiac myocytes. Together with their human transcriptomic analysis and corroborating studies in an RVF mouse model, these data render Wipi1 a potential target for RV-directed HF therapy.
Tzimas C, Rau CD, Buergisser PE, Jean-Louis G Jr, Lee K, Chukwuneke J, Dun W, Wang Y, Tsai EJ. (2019) WIPI1 is a conserved mediator of right ventricular failure. JCI Insight [Epub ahead of print]. [article]