MicroRNA-30 inhibits neointimal hyperplasia by targeting Ca(2+)/calmodulin-dependent protein kinase IIδ (CaMKIIδ).
MicroRNA-30 inhibits neointimal hyperplasia by targeting Ca(2+)/calmodulin-dependent protein kinase IIδ (CaMKIIδ).
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DOI：
10.1038/srep26166
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发表时间：
2016-05-20
影响因子：
4.6
通讯作者：
Singer HA
中科院分区：
文献类型：
--
作者：
Liu YF;Spinelli A;Sun LY;Jiang M;Singer DV;Ginnan R;Saddouk FZ;Van Riper D;Singer HA
多功能Ca 2 +/钙调素依赖性蛋白激酶II δ（CaMKIIδ）促进血管平滑肌（VSM）增殖、迁移和损伤诱导的血管壁新生内膜形成。本研究的目的是检测microRNA-30（miR-30）家族成员是否是血管损伤后CaMKIIδ表达的内源性调节因子，以及miR-30的异位表达是否能抑制血管损伤诱导的CaMKIIδ依赖性VSM细胞功能和新生内膜VSM增生。CaMKIIδ 3′UTR包含一个跨物种高度保守的共有miR-30结合序列。损伤后7天，在VSM中层中观察到miR-30家族成员的显著减少和CaMKIIδ2蛋白表达的增加，而CaMKIIδ mRNA表达无变化。在体外培养的大鼠主动脉VSM细胞中，过表达miR-30 c或miR-30 e可抑制CaMK II δ2蛋白表达约50%，并抑制VSM细胞增殖和迁移。在体内，将miR-30 c慢病毒递送到损伤的大鼠颈动脉中防止了损伤诱导的CaMKIIδ2增加。此外，在损伤的中膜平滑肌中，miR-30 c的慢病毒递送显著抑制了新生内膜形成。这些研究确定了一种调节VSM中CaMKIIδ表达的新机制，并提供了一种新的潜在治疗策略，以减少血管增殖性疾病的进展，包括动脉粥样硬化和再狭窄。
The multifunctional Ca2+/calmodulin-dependent protein kinase II δ-isoform (CaMKIIδ) promotes vascular smooth muscle (VSM) proliferation, migration, and injury-induced vascular wall neointima formation. The objective of this study was to test if microRNA-30 (miR-30) family members are endogenous regulators of CaMKIIδ expression following vascular injury and whether ectopic expression of miR-30 can inhibit CaMKIIδ-dependent VSM cell function and neointimal VSM hyperplasia induced by vascular injury. The CaMKIIδ 3′UTR contains a consensus miR-30 binding sequence that is highly conserved across species. A significant decrease in miR-30 family members and increase in CaMKIIδ2 protein expression, with no change in CaMKIIδ mRNA expression, was observed in medial layers of VSM 7 days post-injury. In vitro, overexpression of miR-30c or miR-30e inhibited CaMKIIδ2 protein expression by ~50% in cultured rat aortic VSM cells, and inhibited VSM cell proliferation and migration. In vivo, lenti-viral delivery of miR-30c into injured rat carotid arteries prevented the injury-induced increase in CaMKIIδ2. Furthermore, neointima formation was dramatically inhibited by lenti-viral delivery of miR-30c in the injured medial smooth muscle. These studies define a novel mechanism for regulating CaMKIIδ expression in VSM and provide a new potential therapeutic strategy to reduce progression of vascular proliferative diseases, including atherosclerosis and restenosis.