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.
Highlights
Vascular smooth muscle (VSM) cells are not terminally differentiated[1,2] and undergo phenotype dynamics during development, wound healing and some occlusive vascular diseases including atherosclerosis, post-angioplasty restenosis, vein graft failure and arteriovenous fistula failure[3,4]
Accumulating evidence demonstrates the importance of signaling by the multifunctional protein kinase calmodulin-dependent protein kinase II δ-isoform (CaMKIIδ)-isoform in regulating VSM cell proliferation and migration, contributing to vascular remodeling during restenosis and hypertension[5,33]
We have demonstrated changes in the relative content of co-expressed CaMKIIδand –γisoforms in VSM associated with phenotype switching following vascular injury or cell culture; changes that have important functional consequences
Summary
Vascular smooth muscle (VSM) cells are not terminally differentiated[1,2] and undergo phenotype dynamics during development, wound healing and some occlusive vascular diseases including atherosclerosis, post-angioplasty restenosis, vein graft failure and arteriovenous fistula failure[3,4]. In VSM, Dicer knockout results in increased CaMKIIδexpression[22] and a function for miR143/145 has been suggested, either directly by regulating CaMKIIδmRNA translation, or indirectly by regulating VSM phenotypic modulation by targeting a network of transcription factors, including Klf[4], myocardin and Elk-123. Lenti-viral rescue of miR-30 in the injured arteries significantly prevented the increase in CaMKIIδexpression and reduced VSM cell proliferation and neointimal formation Taken together, these studies establish negative regulation of CaMKIIδby miR-30 in VSM, and indicate that decreased miR-30 expression associated with VSM phenotype switching is a potential mechanism for regulating vascular remodeling in response to injury
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