Abstract 18991: A Mir-208-mef2 Axis Drives the Decompensation of Right Ventricular Function in Pulmonary Hypertension
Right Ventricular Failure (RVF) is the major cause of morbidity and mortality in PHT but remains understudied compared to left ventricular failure. The transition from a compensated to decompensated RV occurs much earlier in the RV for unknown reasons. RV and LV have different embryology; the Islet1/Mef2/Hand2 axis is specific for RV formation. Mef2 regulates metabolic, contractile and angiogenic genes critical for RV adaptation to pressure overload. MicroRNAs (miRNAs) have emerged as important determinants of LV development and disease, but little is known about RV miRNAs. We hypothesized that a miRNA-Mef2 axis is important in RV decompensation.
We modeled RVF in the rat monocrotaline (MCT) PAH model in a clinical manner, establishing 3 sequential stages of RV response to PAH (n=6/group): a) normal RV at baseline (NRV, RVSP=38±2mmHg, CO=102±2ml/min and RV/LV+Septum=22±1); b) compensated RV (CRV) 3-4weeks post-MCT when mortality is minimal and cardiac output is stable (RVSP=66±8 mmHg, CO=80±13ml/min, RV/LV+Septum=48±3); c) decompensated RV (DRV) 4-6weeks post-MCT when contractility and cardiac output declines while RV size, ascites and mortality increase rapidly (RVSP=52±2mmHg, CO=67±10ml/min, RV/LV+Septum=58±2).
Using unbiased miRNA arrays (n=9), we found that the levels of the cardiac-specific miRNA miR-208 progressively decreased in CRV and DRV, correlating with RV size increase (r=-0.68, n=20, p<0.001); whereas its expression is known to remain stable in models of LV hypertrophy. The level of the miR-208 target, MED13, increased in DRV. MED13, a subunit of the complex mediator of transcription, activates the repressor NCoR1, which deacetylates Mef2 family members, decreasing their transcriptional activity. NCoR1 expression was increased in DRV, while Mef2 expression was decreased. We infected adult cardiomyocytes isolated from CRV free walls with an adenovirus expressing an anti-miR-208. This was associated with increased MED13 and NCoR1 levels, and decreased Mef2 expression, mimicking the transition to DRV in vivo.
We identified an RV-specific miR-208-Mef2 axis characterizing the transition from CRV to DRV, which may lead to the discovery of much-needed biomarkers and treatments of RVF, for which there are currently no treatments.
- © 2013 by American Heart Association, Inc.