MiR-204 regulates type 1 IP3R to control vascular smooth muscle cell contractility and blood pressure
MiR-204 regulates type 1 IP3R to control vascular smooth muscle cell contractility and blood pressure
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DOI：
10.1016/j.ceca.2019.03.006
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发表时间：
2019-06-01
期刊：
影响因子：
4
通讯作者：
Kassan, Modar
中科院分区：
文献类型：
--
作者：
Gabani, Mohanad;Liu, Jing;Kassan, Modar
MiR-204在血管平滑肌细胞（VSMC）中表达。然而，它在VSMC收缩中的作用尚不清楚。我们确定miR-204是否通过调节肌浆网（SR）钙（Ca2+）释放来控制VSMC收缩性和血压。我们比较了miR-204（-/-）小鼠和野生型小鼠（WT）的主动脉和系膜阻力动脉（MRA）的收缩压（SBP）和血管对VSMC收缩激动剂(苯肾上腺素（PE）、血栓素类似物（U46619）、内皮素-1 （ET-1）、血管紧张素-II （Ang II）和去甲肾上腺素（NE）的反应性。两种基因型的基础收缩压（SBP）无差异；然而，与WT小鼠相比，miR-204（-/-）小鼠对Ang II的高血压反应明显更大。miR-204（-/-）小鼠的主动脉和MRA对所有VSMC激动剂具有增强的收缩性。计算机算法预测1型肌醇1,4,5 -三磷酸受体（IP(3)R1）是miR-204的靶标。miR-204（-/-）小鼠的主动脉和MRA中IP(3)R1的表达高于WT小鼠。通过药理抑制IP(3)R1, miR-204（-/-）和WT小鼠之间激动剂诱导的血管收缩的差异被消除。此外，与WT小鼠相比，Ang ii诱导的miR-204（-/-）小鼠的主动脉IP(3)R1更大。此外，在注入Ang II后，miR-204（-/-）和WT小鼠对VSMC激动剂的主动脉血管收缩的差异持续存在。体外VSMC中miR-204的抑制增加了IP(3)R1，并增加了SR Ca2+释放以响应PE，而miR-204的过表达下调了IP(3)R1。最后，靶向miR-204-IP(3)R1相互作用的序列特异性核苷酸阻断剂挽救了mir -204诱导的IP(3)R1下调。我们得出结论，miR-204通过IP(3) r1依赖性调节SR钙释放来控制VSMC收缩性和血压。
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 (Ca2+) 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 (IP(3)R1) as a target of miR-204. Aortas and MRA of miR-204(-/-) mice had higher expression of IP(3)R1 compared to WT mice. Difference in agonist-induced vasoconstriction between miR-204(-/-) and WT mice was abolished with pharmacologic inhibition of IP(3)R1. Furthermore, Ang II-induced aortic IP(3)R1 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 IP(3)R1, and boosted SR Ca2+ release in response to PE, while overexpression of miR-204 downregulated IP(3)R1. Finally, a sequence-specific nucleotide blocker that targets the miR-204-IP(3)R1 interaction rescued miR-204-induced downregulation of IP(3)R1. We conclude that miR-204 controls VSMC contractility and blood pressure through IP(3)R1-dependent regulation of SR calcium release.