| First Author | Chen J | Year | 2021 |
| Journal | J Biol Chem | Volume | 297 |
| Issue | 6 | Pages | 101228 |
| PubMed ID | 34600884 | Mgi Jnum | J:345345 |
| Mgi Id | MGI:7579537 | Doi | 10.1016/j.jbc.2021.101228 |
| Citation | Chen J, et al. (2021) Resistance of Acta2(R149C/+) mice to aortic disease is associated with defective release of mutant smooth muscle alpha-actin from the chaperonin-containing TCP1 folding complex. J Biol Chem 297(6):101228 |
| abstractText | Pathogenic variants of the gene for smooth muscle alpha-actin (ACTA2), which encodes smooth muscle (SM) alpha-actin, predispose to heritable thoracic aortic disease. The ACTA2 variant p.Arg149Cys (R149C) is the most common alteration; however, only 60% of carriers have a dissection or undergo repair of an aneurysm by 70 years of age. A mouse model of ACTA2 p.Arg149Cys was generated using CRISPR/Cas9 technology to determine the etiology of reduced penetrance. Acta2(R149C/+) mice had significantly decreased aortic contraction compared with WT mice but did not form aortic aneurysms or dissections when followed to 24 months, even when hypertension was induced. In vitro motility assays found decreased interaction of mutant SM alpha-actin filaments with SM myosin. Polymerization studies using total internal reflection fluorescence microscopy showed enhanced nucleation of mutant SM alpha-actin by formin, which correlated with disorganized and reduced SM alpha-actin filaments in Acta2(R149C/+) smooth muscle cells (SMCs). However, the most prominent molecular defect was the increased retention of mutant SM alpha-actin in the chaperonin-containing t-complex polypeptide folding complex, which was associated with reduced levels of mutant compared with WT SM alpha-actin in Acta2(R149C/+) SMCs. These data indicate that Acta2(R149C/+) mice do not develop thoracic aortic disease despite decreased contraction of aortic segments and disrupted SM alpha-actin filament formation and function in Acta2(R149C/+) SMCs. Enhanced binding of mutant SM alpha-actin to chaperonin-containing t-complex polypeptide decreases the mutant actin versus WT monomer levels in Acta2(R149C/+) SMCs, thus minimizing the effect of the mutation on SMC function and potentially preventing aortic disease in the Acta2(R149C/+) mice. |
