A miR-208-Mef2 Axis Drives the De-Compensation of Right Ventricular Function in Pulmonary Hypertension
Rationale: Right Ventricular Failure (RVF) is a major cause of morbidity and mortality in pulmonary hypertension (PHT), but its mechanism remains unknown. Myocyte enhancer factor 2 (Mef2) has been implicated in RV development, regulating metabolic, contractile and angiogenic genes. Moreover, Mef2 regulates microRNAs (miRNAs) that have emerged as important determinants of cardiac development and disease, but for which the role in RV is still unclear.
Objective: We hypothesized a critical role of a Mef2-miRNA axis in RVF.
Methods and Results: In a rat PHT model (monocrotaline), we studied RV free-wall tissues from rats with normal (nRV), compensated (cRVH) and de-compensated (dRVH) RV hypertrophy, carefully defined based on clinically-relevant parameters, including RV systolic and end-diastolic pressures, cardiac output, RV size and morbidity. Mef2c expression was sharply increased in cRVH tissues, but was lost in dRVH. An unbiased screening of miRNAs in our model resulted to a short miRNA signature of dRVF, which included the myocardium-specific miR-208; which was progressively down-regulated as RVF progressed, in contrast to what is described in LVF. With mechanistic in vitro experiments using neonatal and adult RV cardiomyocytes we showed that miR-208 inhibition as well as TNFα, activate the MED13/NCoR1 axis, which in turn promotes Mef2 inhibition, closing a self-limiting feed-back loop, driving the transition from cRVH toward dRVH. In our model, serum TNFα levels progressively increased with time while serum miR-208 levels decreased, mirroring its levels in RV myocardium.
Conclusions: We describe an RV-specific mechanism for heart failure, which could potentially lead to new biomarkers and therapeutic targets.
- right ventricle hypertrophy
- right ventricular failure
- right ventricular pressure overload
- pulmonary hypertension
- Received March 9, 2014.
- Revision received September 29, 2014.
- Accepted October 6, 2014.