Discordant Regulation of microRNA Between Multiple Experimental Models and Human Pulmonary Hypertension

The dysregulation of microRNA (miRNA) is known to contribute to the pathobiology of pulmonary arterial hypertension (PAH). However, the relationships between changes in tissue and circulating miRNA levels associated with different animal models and human pulmonary hypertension (PH) have not been defined.

A set of miRNAs that have been causally implicated in PH, including miR-17, -21, -130b, -145, -204, -424, and -503, were measured by reverse transcription-quantitative polymerase chain reaction in the plasma, lung, and right ventricle of three of the most common rodent models of PH: the rat monocrotaline and SU5416 plus chronic hypoxia (SuHx) models and the mouse chronic hypoxia model. Plasma miRNA levels were also evaluated in a cohort of patients with PAH and healthy subjects.

Several miRNA showed PH model-dependent perturbations in plasma and tissue levels; however, none of these were conserved across all three experimental models. Principle component analysis of miR expression changes in plasma revealed distinct clustering between rodent models, and SuHx-triggered PH showed the greatest similarity to human PAH. Changes in the plasma levels of several miRNA also correlated with changes in tissue expression. In particular, miR-424 was concordantly increased (1.3- to 1.5-fold, P < .05) in the plasma, lung, and right ventricle of hypoxic mice and in the plasma of patients with PAH.

miRNAs with established etiologic roles in PH showed context-dependent changes in tissue and circulating levels, which were not consistent across rodent models and human PAH. This suggests different miRNA-dependent mechanisms may contribute to experimental and clinical PH, complicating potential diagnostic and therapeutic applications amenable to these miRNAs.