MiR-449a-5p mediates mitochondrial dysfunction and phenotypic transition by targeting Myc in pulmonary arterial smooth muscle cells.

MicroRNAs have been considered to participate in pulmonary arterial hypertension (PAH) and regulate numerous disease pathways in pulmonary vasculature. However, the molecular role in the pathologies has not yet been fully uncovered, particularly in the view of energy metabolism and vascular smooth muscle cell phenotypic regulation. Here, several altered miRNAs are founded in genome-wide miRNA sequencing analysis, in which miR-449a-5p was identified as a probable candidate in hypoxic PAH and verified such a decreasing trend. Moreover, we identify that miR-449a-5p plays critical role in both mitochondria metabolic dysfunction and phenotype transformation of pulmonary arterial smooth muscle cells. Subsequently, we initiate that the transcription factor Myc, which is negatively regulated by miR-449a-5p, results in the aberrant effects contributing to pulmonary arterial smooth muscle cell proliferation. Taken together, we demonstrated that the miR-449a-5p/Myc axis is indispensable for the development and progression of PAH. These results may serve as a significant implication for understanding and treatment of PAH. KEY MESSAGES: • The downregulation of miR-449a-5p occurs in both PAH-PAs and hypoxic PASMCs. • MiR-449a-5p is involved in hypoxia-induced mitochondria dysfunction of PASMCs. • MiR-449a-5p inhibits hypoxic phenotypic transition and proliferation of PASMCs. • The aberrant effects of MiR-449a-5p depend on downstream transcription factor Myc. • Myc contributes to mitochondria dysfunction and phenotype transformation in PAH.