MicroRNA-153 targeting of KCNQ4 contributes to vascular dysfunction in hypertension
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MicroRNA-153 targeting of KCNQ4 contributes to vascular dysfunction in hypertension. / Carr, Georgina; Barrese, Vincenzo; Stott, Jennifer B; Povstyan, Oleksandr V; Jepps, Thomas A; Figueiredo, Hericka B; Zheng, Dongling; Jamshidi, Yalda; Greenwood, Iain A.
In: Cardiovascular Research, Vol. 112, 07.07.2016, p. 581-589.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - MicroRNA-153 targeting of KCNQ4 contributes to vascular dysfunction in hypertension
AU - Carr, Georgina
AU - Barrese, Vincenzo
AU - Stott, Jennifer B
AU - Povstyan, Oleksandr V
AU - Jepps, Thomas A
AU - Figueiredo, Hericka B
AU - Zheng, Dongling
AU - Jamshidi, Yalda
AU - Greenwood, Iain A
N1 - © The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.
PY - 2016/7/7
Y1 - 2016/7/7
N2 - AIMS: Kv7.4, a voltage-dependent potassium channel expressed throughout the vasculature, controls arterial contraction and is compromised in hypertension by an unknown mechanism. MicroRNAs (miRs) are post-transcriptional regulators of protein production and are altered in disease states such as hypertension. We investigated whether miRs regulate Kv7.4 expression.METHODS AND RESULTS: In renal and mesenteric arteries (MAs) of the spontaneously hypertensive rat (SHR), Kv7.4 protein decreased compared with the normotensive (NT) rat without a decrease in KCNQ4 mRNA, inferring that Kv7.4 abundance was determined by post-transcriptional regulation. In silico analysis of the 3' UTR of KCNQ4 revealed seed sequences for miR26a, miR133a, miR200b, miR153, miR214, miR218, and let-7d with quantitative polymerase chain reaction showing miR153 increased in those arteries from SHRs that exhibited decreased Kv7.4 levels. Luciferase reporter assays indicated a direct targeting effect of miR153 on the 3' UTR of KCNQ4. Introduction of high levels of miR153 to MAs increased vascular wall thickening and reduced Kv7.4 expression/Kv7 channel function compared with vessels receiving a non-targeting miR, providing a proof of concept of Kv7.4 regulation by miR153.CONCLUSION: This study is the first to define a role for aberrant miR153 contributing to the hypertensive state through targeting of KCNQ4 in an animal model of hypertension, raising the possibility of the use of miR153-related therapies in vascular disease.
AB - AIMS: Kv7.4, a voltage-dependent potassium channel expressed throughout the vasculature, controls arterial contraction and is compromised in hypertension by an unknown mechanism. MicroRNAs (miRs) are post-transcriptional regulators of protein production and are altered in disease states such as hypertension. We investigated whether miRs regulate Kv7.4 expression.METHODS AND RESULTS: In renal and mesenteric arteries (MAs) of the spontaneously hypertensive rat (SHR), Kv7.4 protein decreased compared with the normotensive (NT) rat without a decrease in KCNQ4 mRNA, inferring that Kv7.4 abundance was determined by post-transcriptional regulation. In silico analysis of the 3' UTR of KCNQ4 revealed seed sequences for miR26a, miR133a, miR200b, miR153, miR214, miR218, and let-7d with quantitative polymerase chain reaction showing miR153 increased in those arteries from SHRs that exhibited decreased Kv7.4 levels. Luciferase reporter assays indicated a direct targeting effect of miR153 on the 3' UTR of KCNQ4. Introduction of high levels of miR153 to MAs increased vascular wall thickening and reduced Kv7.4 expression/Kv7 channel function compared with vessels receiving a non-targeting miR, providing a proof of concept of Kv7.4 regulation by miR153.CONCLUSION: This study is the first to define a role for aberrant miR153 contributing to the hypertensive state through targeting of KCNQ4 in an animal model of hypertension, raising the possibility of the use of miR153-related therapies in vascular disease.
U2 - 10.1093/cvr/cvw177
DO - 10.1093/cvr/cvw177
M3 - Journal article
C2 - 27389411
VL - 112
SP - 581
EP - 589
JO - Cardiovascular Research
JF - Cardiovascular Research
SN - 0008-6363
ER -
ID: 167175446