EGR1 Is Implicated in Right Ventricular Cardiac Remodeling Associated with Pulmonary Hypertension

SIMPLE SUMMARY: Pulmonary hypertension (PH) is a condition characterized by increased arterial pressure in the pulmonary vasculature. PH strains the right heart, which compensates for the increased afterload by hypertrophy. This eventually leads to heart failure, which represents the leading cause of death in PH patients. Surgeries normalize pulmonary arterial pressures and cause the regeneration of hypertrophic right hearts. Nonetheless, the events involved in cardiac recovery are largely unknown. We therefore investigated the gene expression profiles of hypertrophic and regenerated right hearts of two different types of PH patients. Intriguingly, the PH subtypes displayed a rather unique gene alteration signature, before as well as after surgery. While genes associated with muscle cell development were upregulated in one group, genes involved in the same molecular process were downregulated in a different PH group following surgery. However, we were able to identify a profibrotic factor, namely early growth response 1, in both PH groups. A role for this molecule in hypertrophic right hearts was further confirmed by immunohistochemistry. In conclusion, our study described the gene expression signatures of failing and recovered right hearts of PH patients. The findings presented here might help to identify attractive therapeutic candidates for PH patients considered inoperable. ABSTRACT: Background: Pulmonary hypertension (PH) is a vasoconstrictive disease characterized by elevated mean pulmonary arterial pressure (mPAP) at rest. Idiopathic pulmonary arterial hypertension (iPAH) and chronic thromboembolic pulmonary hypertension (CTEPH) represent two distinct subtypes of PH. Persisting PH leads to right ventricular (RV) hypertrophy, heart failure, and death. RV performance predicts survival and surgical interventions re-establishing physiological mPAP reverse cardiac remodeling. Nonetheless, a considerable number of PH patients are deemed inoperable. The underlying mechanism(s) governing cardiac regeneration, however, remain largely elusive. Methods: In a longitudinal approach, we profiled the transcriptional landscapes of hypertrophic RVs and recovered hearts 3 months after surgery of iPAH and CTEPH patients. Results: Genes associated with cellular responses to inflammatory stimuli and metal ions were downregulated, and cardiac muscle tissue development was induced in iPAH after recovery. In CTEPH patients, genes related to muscle cell development were decreased, and genes governing cardiac conduction were upregulated in RVs following regeneration. Intriguingly, early growth response 1 (EGR1), a profibrotic regulator, was identified as a major transcription factor of hypertrophic RVs in iPAH and CTEPH. A histological assessment confirmed our biocomputational results, and suggested a pivotal role for EGR1 in RV vasculopathy. Conclusion: Our findings improved our understanding of the molecular events driving reverse cardiac remodeling following surgery. EGR1 might represent a promising candidate for targeted therapy of PH patients not eligible for surgical treatment.