Abstract 18277: Role of the miR-204/miR-145 Communication in the Etiology of Pulmonary Arterial Hypertension

Abstract

Introduction: Pulmonary arterial hypertension (PAH) is characterized by distal pulmonary arteries remodeling secondary to the proliferation and resistance to apoptosis of the pulmonary artery smooth muscle (PASMC). We recently described that this phenotype is associated with 7 aberrantly expressed miRNAs in PAH-PASMC. We showed that miR-204 was the most downregulated and accounts for the activation of the neoplasic axis STAT3/Pim1/NFAT, inducing PASMC proliferation and resistance to apoptosis. Because miR-204 downregulation precedes the development of PAH in chronic hypoxic mice and monocrotaline rats, we tested whether its downregulation accounts for the deregulation of the 6 others affected miRNAs in PAH. As miR-145 is implicated in systemic vascular remodeling and is the one of the most upregulated miRNA in PAH we focused our research on the regulation of miR-145 by miR-204. Methods/Results: Using lungs biopsies from 8 PAH and 8 control patients we confirmed the downregulation of miR-204 and the upregulation of miR-145 in PAH. Moreover, both miR-204 downregulation and miR-145 upregulation correlate with PAH severity. These findings were confirmed in both lungs and distal PAs of 5-MCT and 5 Sugen/Hypoxia/Normoxia rats compare to 5 control rats in which severity was assessed by CT-scan angiogram. Time to event analysis in both monocrotaline (1; 2; 3 and 4 weeks post MCT injection) and Sugen (8 and 15 weeks post Sugen) rats showed that miR-204 downregulation precedes miR-145 upregulation. In vitro using cultured human PASMC from 5 control and 3 PAH patients we showed that miR-204 upregulation in PAH-PASMC decreases miR-145; while miR-204 downregulation in control PASMC increases miR-145. Finally, in vivo nebulized MCT rats with miR-204 mimic had significantly less miR-145 compared to rats nebulized with mimic negative control. Conclusion: We demonstrated for the first time in PAH that one miRNA (miR-204) can regulate the expression of other miRNA such as miR-145. Because miR-204 downregulation precede miR-145 upregulation and PAH development, miR-204 could be considered as an early molecular marker of PAH and might represent the molecular origin of this lethal disease.