Novel treatment target found for RV failure in PAH

Aug 10 2015

By Lucy Piper, Senior medwireNews Reporter

Researchers have identified a molecular pathway by which downregulation of microRNA (miR)-126 contributes to right ventricular (RV) failure in patients with pulmonary arterial hypertension (PAH).

Downregulation of the microRNA was found to decrease angiogenesis and microvessel density and promote transition from compensated RV hypertrophy to decompensated RV hypertrophy in PAH.

Moreover, the team reports in Circulation that in primary cultured endothelial cells isolated from patients with decompensated RV failure, restoring miR-126 in vitro reversed the loss of angiogenesis while in vivo injection of mimic miR-126 improved RV function in rats with monocrotaline-induced PAH.

“Thus, our study demonstrates the importance of miR-126 as a new therapeutic target for RV failure in human PAH”, say Sebastien Bonnet (Laval University, Quebec, Canada) and colleagues.

The researchers studied the RV free wall tissue of 17 individuals with normal RV function, eight with compensated RV hypertrophy and 14 PAH patients with decompensated RV failure.

RV tissue from PAH patients showed significantly decreased capillary density compared with those from patients with compensated RV hypertrophy and normal individuals, whereas left ventricle capillary density was unaffected.

The team notes that the decreased capillary density in RV failure was not due to downregulation of vascular endothelial growth factor (VEGF) or VEGFR2 protein expression, rather it was associated with a significantly decreased miR-126 expression, which affects VEGF signalling downstream of the VEGF2 receptor. Levels of this protein in the left ventricle did not differ from those in the other two groups.

Downregulation of miR-126 expression in decompensated RV tissue was associated with a significant upregulation of Sprouty-related protein 1 (SPRED-1), a direct target of miR-126 and a repressor of the VEGF pathway.

Upregulation of SPRED-1, in turn, inhibited the mitogen-activated protein kinase pathway by preventing the binding of RAF1, levels of which were significantly lower in decompensated RV tissue compared with compensated RV tissue, and decreased angiogenesis.

But suppressed angiogenic potential was restored in human endothelial cells isolated from the RV tissues when miR-126 was upregulated, and the use of a silencer against SPRED-1 confirmed that this miR-126 effect was SPRED-1 dependent.

The researchers found that neither hypoxia, tumour necrosis factor nor interleukin-6 were associated with the downregulation of miR-126, but observed that hydralazine, by inhibiting DNA methyl transferase, contributed to its upregulation.

They also showed that downregulation of miR-126 exacerbated RV failure in rats with monocrotaline-induced PAH who were in the compensated RV hypertrophy state, but RV function was maintained with intravenous miR-126 injection.

This maintenance of RV function was associated with decreased RV capillary density, decreased blood pressure and increased cardiac output.

Given recent evidence citing the safety of microRNA-based therapies in humans, the researchers believe their study “opens the door to new avenues of investigation and potentially future RV-specific therapies in PAH.”

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