Journal
CIRCULATION RESEARCH
Volume 110, Issue 11, Pages 1411-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.111.261743
Keywords
MYH11; smooth muscle myosin heavy chain; thoracic aortic aneurysms and dissections; smooth muscle differentiation; mouse model
Funding
- Whitaker Foundation
- Richard T. Pisani Funds
- Center for Clinical and Translational Sciences
- National Institutes of Health from the National Center for Research Resources [TL1 RR024147]
- [P50HL083794-01]
- [R01 HL62594]
- [R01 HL26043]
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Rationale: Mutations in myosin heavy chain (MYH11) cause autosomal dominant inheritance of thoracic aortic aneurysms and dissections. At the same time, rare, nonsynonymous variants in MYH11 that are predicted to disrupt protein function but do not cause inherited aortic disease are common in the general population and the vascular disease risk associated with these variants is unknown. Objective: To determine the consequences of the recurrent MYH11 rare variant, R247C, through functional studies in vitro and analysis of a knock-in mouse model with this specific variant, including assessment of aortic contraction, response to vascular injury, and phenotype of primary aortic smooth muscle cells (SMCs). Methods and Results: The steady state ATPase activity (actin-activated) and the rates of phosphate and ADP release were lower for the R247C mutant myosin than for the wild-type, as was the rate of actin filament sliding in an in vitro motility assay. Myh11(R247C/R247C) mice exhibited normal growth, reproduction, and aortic histology but decreased aortic contraction. In response to vascular injury, Myh11(R247C/R247C) mice showed significantly increased neointimal formation due to increased SMC proliferation when compared with the wild-type mice. Primary aortic SMCs explanted from the Myh11(R247C/R247C) mice were dedifferentiated compared with wild-type SMCs based on increased proliferation and reduced expression of SMC contractile proteins. The mutant SMCs also displayed altered focal adhesions and decreased Rho activation, associated with decreased nuclear localization of myocardin-related transcription factor-A. Exposure of the Myh11(R247C/R247C) SMCs to a Rho activator rescued the dedifferentiated phenotype of the SMCs. Conclusions: These results indicate that a rare variant in MYH11, R247C, alters myosin contractile function and SMC phenotype, leading to increased proliferation in vitro and in response to vascular injury. (Circ Res. 2012;110:1411-1422.)
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