Myocardin regulates vascular response to injury through miR-24/-29a and platelet-derived growth factor receptor-β.

Abstract

OBJECTIVE:

Myocardin, a potent transcriptional coactivator of serum response factor, is involved in vascular development and promotes a contractile smooth muscle phenotype. Myocardin levels are reduced during vascular injury, in association with phenotypic switching of smooth muscle cells (SMCs). However, the direct role of myocardin in vascular disease is unclear.

APPROACH AND RESULTS:

We show that re-expression of myocardin prevents the vascular injury response in murine carotid arteries, with reduced neointima formation due to decreased SMC migration and proliferation. Myocardin reduced SMC migration by downregulating platelet-derived growth factor receptor-β (PDGFRB) expression. Pdgfrb was regulated by myocardin-induced miR-24 and miR-29a expression, and antagonizing these microRNAs restored SMC migration. Furthermore, using miR-24 and miR-29a mimics, we demonstrated that miR-29a directly regulates Pdgfrb expression at the 3' untranslated region while miR-24 has an indirect effect on Pdgfrb levels. Myocardin heterozygous-null mice showed an augmented neointima formation with increased SMC migration and proliferation, demonstrating that endogenous levels of myocardin are a critical regulator of vessel injury responses.

CONCLUSIONS:

Our results extend the function of myocardin from a developmental role to a pivotal regulator of SMC phenotype in response to injury, and this transcriptional coactivator may be an attractive target for novel therapeutic strategies in vascular disease.

• Authors: Amarnath Talasila, Haixiang Yu, Matthew Ackers-Johnson, Martine Bot, Theo van Berkel, Martin R Bennett, Ilze Bot, Sanjay Sinha
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 33 Issue 10 Pg. 2355-65 (Oct 2013) ISSN: 1524-4636 [Electronic] United States
• PMID: 23825366 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3' Untranslated Regions
• Apolipoproteins E
• MIRN24 microRNA, rat
• MIRN29 microRNA, mouse
• MIRN29 microRNA, rat
• MicroRNAs
• Mirn24 microRNA, mouse
• Nuclear Proteins
• Trans-Activators
• myocardin
• Receptor, Platelet-Derived Growth Factor beta

Topics

• 3' Untranslated Regions
• Animals
• Apolipoproteins E (deficiency, genetics)
• Carotid Artery Injuries (genetics, metabolism, pathology, prevention & control)
• Carotid Artery, Common (metabolism, pathology)
• Carotid Stenosis (genetics, metabolism, pathology, prevention & control)
• Cell Movement
• Cell Proliferation
• Cells, Cultured
• Disease Models, Animal
• Gene Expression Regulation
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• MicroRNAs (metabolism)
• Muscle, Smooth, Vascular (injuries, metabolism, pathology)
• Myocytes, Smooth Muscle (metabolism, pathology)
• Neointima
• Nuclear Proteins (deficiency, genetics, metabolism)
• Rats
• Rats, Wistar
• Receptor, Platelet-Derived Growth Factor beta (genetics, metabolism)
• Signal Transduction
• Time Factors
• Trans-Activators (deficiency, genetics, metabolism)
• Transfection