Abstract P174: Nuclear Smooth Muscle α-actin Is Critical For Smooth Muscle Cell Differentiation And To Prevent Cerebrovascular Disease
| Autor: | Callie Kwartler, Xue-yan Duan, Shuangtao Ma, Anita Kaw, Caroline Kernell, Charis Wang, Jiyuan Chen, Xuetong Shen, Dianna M Milewicz |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 41 |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvb.41.suppl_1.p174 |
| Popis: | Missense mutations in ACTA2, encoding α-smooth muscle actin (α-SMA), predispose to thoracic aortic aneurysms. A subset of these ACTA2 mutations also predispose to childhood onset cerebrovascular disease characterized by occlusion of the distal internal carotid arteries and small vessel disease. In our studies to identify how specific ACTA2 mutations predispose to cerebrovascular disease, we confirmed that α-SMA translocates to the nucleus in wildtype (WT) smooth muscle cells (SMCs), is enriched in the nucleus over β-actin with differentiation of SMCs, associates with the INO80 chromatin remodeling complex, and selectively binds to the promoters of SMC contractile genes. Expression of individual mutant α-SMAs in 293 cells determined that missense mutations associated with cerebrovascular disease inhibit this nuclear translocation. To further examine the effects of reduced nuclear α-SMA with ACTA2 mutations, we used two model systems: pluripotent stem cell-derived SMCs from patients with ACTA2-associated cerebrovascular disease (ACTA2 R179C) as well as SMCs explanted from a knockin mouse model (Acta2SMC-R179C/+). Both mouse and human cells harboring the R179C mutation proliferate and migrate more than WT SMCs, are less differentiated than WT SMCs, and have increased expression of pluripotency-associated genes. Although the mutation is heterozygous, these cells show a dominant negative impact on nuclear α-SMA function through dramatically reduced levels of α-SMA in the nucleus, in the INO80 chromatin remodeling complex, and on the promoters of SMC-specific genes. Finally, forced nuclear localization of α-SMA in WT SMCs increases levels of SMC contractile proteins. Taken together, we have identified a novel role for α-SMA in driving differentiation of SMCs, and our data supports that defects in this nuclear role drive cellular phenotypes consistent with the cerebrovascular disease seen in patients with ACTA2 R179 mutations. |
| Databáze: | OpenAIRE |
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