MicroRNA-30 inhibits neointimal hyperplasia by targeting Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ)

Abstract

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.

The microRNA miR‐124 inhibits vascular smooth muscle cell proliferation by targeting S100 calcium‐binding protein A4 (S100A4)

“…In addition, other micro-RNAs have been found to regulate neointimal hyperplasia. For example, miR-663 via transcription factor JunB and myosin light chain 9 [41], miR-145 through Kr€ uppel-like factor 5 [42], miR-30 via CaMKIId [43], and miR-191 through Egr-1 [44]. Likewise, our group also reported two microRNAs that reduce neointimal formation, miR-132 and miR-34c, which target Lrrfip1 and stem cell factor, respectively [12,13].…”

3′-UTR SNP rs2229611 in G6PC1 affects mRNA stability, expression and Glycogen Storage Disease type-Ia risk

“…It is interesting to highlight here that miR-30 family members are generally known as tumor suppressors. 49,50 For instance, miR-30b expression is frequently down regulated in HCC tissues and cell lines and served as a tumor-suppressor and autophagy inhibitor. 50 In colorectal cancer (CRC), miR-30b expression was down-regulated in CRC, which is accompanied with tumorigenesis due to their inability in inhibiting three targets: KRAS, PI3KCD and BCL2.…”

MicroRNA‐30e‐5p promotes cell growth by targeting PTPN13 and indicates poor survival and recurrence in lung adenocarcinoma

“…MicroRNAs as small non‐coding RNAs of approximately 18–25 nucleotides play critical roles in post‐transcriptional gene regulation in various diseases. One particular microRNA, miR‐30e, was previously reported to be implicated in regulating vascular diseases such as neointimal hyperplasia by targeting Ca(2+)/calmodulin‐dependent protein kinase IIδ and mesenchymal stem cells and aortic smooth muscle cells by targeting IGF2 . Based on different tumour histopathological types, miR‐30e showed differential expression in different cancer types.…”