MiRNA‐29b Directly Downregulates K+ Channel Expression and Function in IPAH‐PASMC

Abstract

Downregulation of K+ channel expression and function in pulmonary artery smooth muscle cells (PASMC) is linked to the development of pulmonary vascular remodeling and sustained vasoconstriction in patients with idiopathic pulmonary arterial hypertension (IPAH). However, the underlying mechanism involved in attenuating K+ current (IK) in IPAH‐PASMC remains unclear. MicroRNAs (miRNA), which are small non‐coding RNA that post transcriptionally regulate gene expression, have been implicated in the development and progression of IPAH. In this study, we sought to determine whether miR‐29b, which is upregulated in IPAH, attenuates K+ channel expression and function. In silico analysis revealed complimentary binding sites for miR‐29b on KCNA5 and KCNMA1. Western blot analysis and luciferase assays further showed that miR‐29b directly targets and regulates K+ channel expression in IPAH‐PASMC. Overexpression of miR‐29b in normal PASMC significantly decreased Kv1.5 expression and whole‐cell IK(V) while inhibition of miR‐29b in IPAH‐PASMC rescued Kv1.5 expression and IK(V). Additionally, overexpression of miR‐29b in normal PASMC was shown to decrease whole‐cell currents through Ca2+‐activated K+ channels (BKCa channels), while inhibition of miR‐29b in IPAH‐PASMC rescued IBK(Ca). These data suggest that upregulated miR‐29b is directly involved in downregulating K+ channel expression and attenuating IK in IPAH‐PASMC. NIH Grant: HL115014, HL066012 and HL098053.