MicroRNA-153 targeting of KCNQ4 contributes to vascular dysfunction in hypertension

Abstract

AimsKv7.4, 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 resultsIn 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.ConclusionThis 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.

Kv7 potassium channels as signal transduction intermediates in the control of microvascular tone

“…A similar miRNA‐mediated downregulation of Kv7 channels has been proposed as a contributor to hypertension‐associated vascular remodeling. In this case, miR‐153 was found to be upregulated in thoracic aortae and in RAs and MAs of SHR relative to normotensive Wistar rats, inversely correlating with Kv7.4 protein levels, which were decreased in the SHR arteries . Downregulation of Kv7.4 protein expression in arteries from hypertensive animals has been reported in several studies, although KCNQ4 mRNA levels measured by qRT‐PCR were either increased or decreased .…”

“…Carr et al argue that post‐transcriptional regulation of Kv7.4 by miR‐153 explains the decrease in Kv7.4 protein despite inconsistent effects on KCNQ4 mRNA levels. The initiating signal for miR‐153 expression is not entirely clear, as the expression was dependent on the vascular bed, with MCAs from SHR exhibiting no increase in miR‐153 (consistent with the absence of a difference in Kv7.4 expression in these arteries;). This observation might suggest that mechanotransduction of the elevated pressure in SHRs is not driving miR‐153 expression, as the MCAs would likely experience the same elevated pressures.…”

Activation of Kv7 channels as a novel mechanism for NO/cGMP‐induced pulmonary vasodilation

“…In fact, impairment of this classic pathway at any level is known to importantly contribute to the pathophysiology of PH (Klinger & Kadowitz, ; Schermuly et al, ). Detrimental effects of vascular K v 7 loss have been reported in experimental models of essential hypertension (Barrese et al, ; Carr et al, ; Jepps et al, ) and diabetes (Morales‐Cano et al, , ). Likewise, several studies suggest that K v 7 channels may also be impaired in murine models of PH (Morales‐Cano et al, ; Morecroft, Murray, Nilsen, Gurney, & MacLean, ; Sedivy et al, ).…”

“…Detrimental effects of vascular K v 7 loss have been reported in experimental models of essential hypertension (Barrese et al, 2018;Carr et al, 2016;Jepps et al, 2011) and diabetes (Morales-Cano et al, 2015. Likewise, several studies suggest that K v 7 channels may also be impaired in murine models of PH (Morales-Cano et al, 2014;Morecroft, Murray, Nilsen, Gurney, & MacLean, 2009;Sedivy et al, 2015).…”

Perivascular adipose tissue and the dynamic regulation of Kv7 and Kir channels: Implications for resistant hypertension

“…Another therapeutic strategy could be to increase the expression of VSMC Kir2.1 in the vessel wall, for example, by micro‐RNA–related therapies. In this regard, it is noteworthy that miR153 has been identified to contribute to the hypertensive state through targeting of KCNQ4 . A similar miRNA‐mediated down‐regulation of KCNQ channels, possibly of KCNQ5 mRNA, has been proposed as a contributor to hypoxic pulmonary vasoconstriction .…”