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MiR-204 regulates type 1 IP 3 R to control vascular smooth muscle cell contractility and blood pressure.

Research paper by Mohanad M Gabani, Jing J Liu, Karima K Ait-Aissa, Olha O Koval, Young-Rae YR Kim, Diana D Castañeda, Ajit A Vikram, Julia S JS Jacobs, Isabella I Grumbach, Mohamed M Trebak, Kaikobad K Irani, Modar M Kassan

Indexed on: 31 May '19Published on: 30 Mar '19Published in: Cell Calcium



Abstract

MiR-204 is expressed in vascular smooth muscle cells (VSMC). However, its role in VSMC contraction is not known. We determined if miR-204 controls VSMC contractility and blood pressure through regulation of sarcoplasmic reticulum (SR) calcium (Ca) release. Systolic blood pressure (SBP) and vasoreactivity to VSMC contractile agonists (phenylephrine (PE), thromboxane analogue (U46619), endothelin-1 (ET-1), angiotensin-II (Ang II) and norepinephrine (NE) were compared in aortas and mesenteric resistance arteries (MRA) from miR-204 mice and wildtype mice (WT). There was no difference in basal systolic blood pressure (SBP) between the two genotypes; however, hypertensive response to Ang II was significantly greater in miR-204 mice compared to WT mice. Aortas and MRA of miR-204 mice had heightened contractility to all VSMC agonists. In silico algorithms predicted the type 1 Inositol 1, 4, 5-trisphosphate receptor (IPR1) as a target of miR-204. Aortas and MRA of miR-204 mice had higher expression of IPR1 compared to WT mice. Difference in agonist-induced vasoconstriction between miR-204 and WT mice was abolished with pharmacologic inhibition of IPR1. Furthermore, Ang II-induced aortic IPR1 was greater in miR-204 mice compared to WT mice. In addition, difference in aortic vasoconstriction to VSMC agonists between miR-204 and WT mice persisted after Ang II infusion. Inhibition of miR-204 in VSMC in vitro increased IPR1, and boosted SR Ca release in response to PE, while overexpression of miR-204 downregulated IPR1. Finally, a sequence-specific nucleotide blocker that targets the miR-204-IPR1 interaction rescued miR-204-induced downregulation of IPR1. We conclude that miR-204 controls VSMC contractility and blood pressure through IPR1-dependent regulation of SR calcium release. Copyright © 2019 Elsevier Ltd. All rights reserved.

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