Arteriosclerosis, thrombosis, and vascular biology · 2025
Focal Adhesion Kinase Promotes Calcification of Vascular Smooth Muscle Cells via Regulation of Histone Deacetylase 4 and 5.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Tian Wenjie, Singh Kuldeep, Kajuluri Lova P, Lu Jing, Lee Sujin, Roh Kangsan, Nicholson Christopher J, Jiang Wanlin, Barnes Hanna J, Sato Tadatoshi, Boerboom Sophie, Ostrom Katrina, Li Rebecca H, Birchenough Claire, Moore Elizabeth, Tattersfield Helena, Sigurslid Haakon H, Mahamdeh Mohammed S, Mosquera Jose V, Hodonsky Chani J, Johnson Adam L, Chou Elizabeth L, Nigwekar Sagar, Lindsay Mark E, Bloch Donald B, Lino Cardenas Christian L, Ichinose Fumito, Miller Clint L, Wein Marc N, Malhotra Rajeev
Аннотация
BACKGROUND: Vascular calcification is an active process driven by osteogenic phenotypic transition of vascular smooth muscle cells (VSMCs) and regulated by a bone-related gene regulatory network. Recent studies showed that FAK (focal adhesion kinase) regulates bone formation by affecting the cellular localization of HDAC (histone deacetylase) 4 and HDAC5. However, it is not known whether FAK exerts effects on vascular calcification in VSMCs through regulating HDACs.
METHODS: We used perturbational assays to assess the role of HDAC4, HDAC5, and FAK in VSMC calcification. Pharmacological inhibition and gene silencing of FAK were used to evaluate effects on calcification, cell migration, and the expression of procalcification factors. Leptomycin was used to inhibit the nuclear export of HDACs. In addition, ex vivo cultures of mouse and human arteries were treated with a FAK inhibitor to assess effects on arterial calcification. Single-cell transcriptomic expression of FAK was examined in healthy and diseased human coronary arteries.
RESULTS: HDAC4 and HDAC5 were identified as positive regulators of vascular calcification. Pharmacological inhibition or gene silencing of FAK blocked VSMC calcification, abrogated the osteogenic medium-induced elevation of procalcification factors, and reduced cell migration. FAK inhibition reduced HDAC4 and HDAC5 phosphorylation and enhanced nuclear localization of these HDAC proteins. Inhibition of HDAC4 and HDAC5 nuclear export with leptomycin showed similar effects on calcification as FAK inhibition. Treatment with the FAK inhibitor attenuated the calcification of ex vivo mouse and human arteries. FAK gene expression was dysregulated in human diseased coronary arteries compared with healthy coronary arteries, and, in single-cell analysis of human arterial tissue, FAK expression was highest in VSMCs at an intermediate state between contractile and osteogenic phenotypes.
CONCLUSIONS: FAK promotes VSMC calcification, at least in part, via phosphorylation of HDAC4 and HDAC5. Targeted regulation of the activity of FAK, HDAC4, and HDAC5 may be an effective strategy for the treatment of vascular calcification.
METHODS: We used perturbational assays to assess the role of HDAC4, HDAC5, and FAK in VSMC calcification. Pharmacological inhibition and gene silencing of FAK were used to evaluate effects on calcification, cell migration, and the expression of procalcification factors. Leptomycin was used to inhibit the nuclear export of HDACs. In addition, ex vivo cultures of mouse and human arteries were treated with a FAK inhibitor to assess effects on arterial calcification. Single-cell transcriptomic expression of FAK was examined in healthy and diseased human coronary arteries.
RESULTS: HDAC4 and HDAC5 were identified as positive regulators of vascular calcification. Pharmacological inhibition or gene silencing of FAK blocked VSMC calcification, abrogated the osteogenic medium-induced elevation of procalcification factors, and reduced cell migration. FAK inhibition reduced HDAC4 and HDAC5 phosphorylation and enhanced nuclear localization of these HDAC proteins. Inhibition of HDAC4 and HDAC5 nuclear export with leptomycin showed similar effects on calcification as FAK inhibition. Treatment with the FAK inhibitor attenuated the calcification of ex vivo mouse and human arteries. FAK gene expression was dysregulated in human diseased coronary arteries compared with healthy coronary arteries, and, in single-cell analysis of human arterial tissue, FAK expression was highest in VSMCs at an intermediate state between contractile and osteogenic phenotypes.
CONCLUSIONS: FAK promotes VSMC calcification, at least in part, via phosphorylation of HDAC4 and HDAC5. Targeted regulation of the activity of FAK, HDAC4, and HDAC5 may be an effective strategy for the treatment of vascular calcification.