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miR-1 Is Increased in Pulmonary Hypertension and Downregulates Kv1.5 Channels in Rat Pulmonary Arteries

miR-1 Is Increased in Pulmonary Hypertension and Downregulates Kv1.5 Channels in Rat Pulmonary Arteries

Gema Mondejar-Parreño, María Callejo, Bianca Barreira, Daniel Morales-Cano, Sergio Esquivel-Ruiz, Laura Moreno, Angel Cogolludo, Francisco Perez-Vizcaino

J Physiol. 2019 Feb;597(4):1185-1197.

PMID: 29717493

Abstract:

Key points:
The expression of miR-1 is increased in lungs from the Hyp/Su5416 PAH rat model. Pulmonary artery smooth muscle cells from this animal model are more depolarized and show decreased expression and activity of voltage-dependent potassium channel (Kv)1.5. miR-1 directly targets Kv1.5 channels, reduces Kv1.5 activity and induces membrane depolarization. Antagomir-1 prevents Kv1.5 channel downregulation and the depolarization induced by hypoxia/Su5416 exposition.
Abstract:
Impairment of the voltage-dependent potassium channel (Kv) plays a central role in the development of cardiovascular diseases, including pulmonary arterial hypertension (PAH). MicroRNAs are non-coding RNAs that regulate gene expression by binding to the 3'-untranslated region region of specific mRNAs. The present study aimed to analyse the effects of miR-1 on Kv channel function in pulmonary arteries (PA). Kv channel activity was studied in PA from healthy animals transfected with miR-1 or scrambled-miR. Kv currents were studied using the whole-cell configuration of the patch clamp technique. The characterization of the Kv1.5 currents was performed with the selective inhibitor DPO-1. miR-1 expression was increased and Kv1.5 channels were decreased in lungs from a rat model of PAH induced by hypoxia and Su5416. miR-1 transfection increased cell capacitance, reduced Kv1.5 currents and induced membrane depolarization in isolated pulmonary artery smooth muscle cells. A luciferase reporter assay indicated that KCNA5, which encodes Kv1.5 channels, is a direct target gene of miR-1. Incubation of PA with Su5416 and hypoxia (3% O2 ) increased miR-1 and induced a decline in Kv1.5 currents, which was prevented by antagomiR-1. In conclusion, these data indicate that miR-1 induces pulmonary artery smooth muscle cell hypertrophy and reduces the activity and expression of Kv channels, suggesting a pathophysiological role in PAH.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP43077301	DPO-1		43077-30-1	Price

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