Increased Expression of MicroRNA‐206 Inhibits Potassium Voltage‐Gated Channel Subfamily A Member 5 in Pulmonary Arterial Smooth Muscle Cells and Is Related to Exaggerated Pulmonary Artery Hypertension Following Intrauterine Growth Retardation in Rats

Abstract

Background Intrauterine growth retardation ( IUGR ) is related to pulmonary artery hypertension in adults, and mi croRNA ‐206 (miR‐206) is proposed to affect the proliferation and apoptosis of pulmonary artery smooth muscle cells ( PASMC s) via post‐transcriptional regulation. Methods and Results In an IUGR rat model, we found that the expression and function of potassium voltage‐gated channel subfamily A member 5 (Kv1.5) in PASMC s was inhibited, and pulmonary artery hypertension was exaggerated after chronic hypoxia ( CH ) treatment as adults. micro RNA expression was investigated in PASMC s from 12‐week‐old male IUGR rats with CH by microarray, polymerase chain reaction, and in situ hybridization. The expression levels of Kv1.5 in primary cultured PASMC s and pulmonary artery smooth muscle from IUGR or control rats were evaluated with and without application of an miR‐206 inhibitor. Right ventricular systolic pressure, cell proliferation, luciferase reporter assay, and I K v were also calculated. We found increased expression of miR‐206 in resistance pulmonary arteries of IUGR rats at 12 weeks compared with newborns. Application of an miR‐206 inhibitor in vivo or in vitro increased expression of Kv1.5 α‐protein and KCNA 5. Also, decreased right ventricular systolic pressure and cell proliferation were observed in PASMC s from 12‐week‐old control and IUGR rats after CH , while inhibitor did not significantly affect control and IUGR rats. Conclusions These results suggest that expression of Kv1.5 and 4‐aminopyridine (Kv channel special inhibitor)‐sensitive Kv current were correlated with the inhibition of miR‐206 in PA rings of IUGR ‐ CH rats and cultured IUGR PASMC s exposed to hypoxia. Thus, miR‐206 may be a trigger for induction of exaggerated CH–pulmonary artery hypertension of IUGR via Kv1.5.

The Role and Regulation of Pulmonary Artery Smooth Muscle Cells in Pulmonary Hypertension

“…However, the exact mechanisms by which K + channels act on PASMC are still controversial [ 41 – 51 ]. Lv et al found increased expression of MicroRNA-206 suppressed potassium voltage-gated channel subfamily A member 5 (Kv1.5) and promoted the PASMC proliferation [ 52 ].…”

“…However, the exact mechanisms by which K + channels act on PASMC are still controversial[41][42][43][44][45][46][47][48][49][50][51]. Lv et al found increased expression of MicroRNA-206 suppressed potassium voltage-gated channel subfamily A member 5 (Kv1.5) and promoted the PASMC proliferation[52].e elevated concentration of intracellular Ca 2+ was found in PAH animal models and patients.is kind of phenomenon was not realized through activation of voltagegated calcium channels (VGCC), but by increase of canonical transient receptor potential (TRPC) proteins, which involved Ca 2+ -permeable nonselective cation channels (NSCCs). Increased abundance of NSCCs was detected in PAH rat models and patients and inhibition of NSCCs, either pharmacologically or by RNA silencing, effectively decreased the concentration of intracellular Ca 2+ and proliferation of PASMC[53][54][55][56][57][58][59][60][61].…”

The mechanism of ions in pulmonary hypertension

“…76–78 Other factors that regulate cell proliferation, such as microRNA and mitogen, also regulate cell proliferation by down-regulating the expression of Kv1.5. 79,80 Kv channel can not only promote cell proliferation, but also inhibit apoptosis. It has been found that after inhibiting the anti-apoptotic protein Survivin, the expression of Kv1.5 and Kv2.1 was up-regulated, and the apoptosis of PASMCs was promoted in the model of PH.…”

MicroRNA-137 Inhibited Hypoxia-Induced Proliferation of Pulmonary Artery Smooth Muscle Cells by Targeting Calpain-2

“…Transient transfection of a Kv channel or a K + channel activator increases K + efflux to enhance PASMC death [ 45 , 46 ]. The decrease of K + channel expression, such as Kv1.5 and Kv1.2, leads to the proliferation of PASMCs [ 47 ]. The opening of potassium channels promotes cell membrane hyperpolarization and reduces calcium overload.…”