FoxO3 normalizes Smad3-induced arterial smooth muscle cell growth.
FoxO3 normalizes Smad3-induced arterial smooth muscle cell growth.
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DOI：
10.3389/fphys.2023.1136998
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发表时间：
2023
影响因子：
4
通讯作者：
Tulis, David A.
中科院分区：
文献类型：
--
作者：
Francisco, Jake T.;Holt, Andrew W.;Bullock, Michael T.;Williams, Madison D.;Poovey, Cere E.;Holland, Nathan A.;Brault, Jeffrey J.;Tulis, David A.
关键词：
动脉平滑肌（ASM）从静止收缩状态过渡到促进生长状态是心血管疾病（CVD）的标志，心血管疾病是美国和世界范围内导致死亡和残疾的主要原因。虽然许多个体信号已被确定为这种表型转化的重要机制，但转录因子Smad3和FoxO3在ASM生长中的综合影响尚不清楚。本研究的目的是确定Smad3和FoxO3在控制ASM细胞生长中是否存在协调的、磷酸化特异性的关系。通过大鼠体内动脉损伤模型和大鼠原代ASM细胞裂解物和组分，验证了分别处于静止和生长状态的低血清和高血清体外模型，以及Smad3和/或FoxO3单独和联合过表达（OE）的腺病毒（Ad-）基因传递，我们假设FoxO3可以调节Smad3诱导的ASM细胞生长。关键发现揭示了Smad3和FoxO3在生长条件下的独特细胞分布，细胞核和细胞质中均可诱导Smad3，但细胞质中主要诱导FoxO3；Ad-Smad3 OE导致磷酸化和总Smad3的胞质和细胞核表达，在静止和生长条件下，Ad-FoxO3共同感染几乎完全逆转这两种表达；Ad-FoxO3 OE导致磷酸化FoxO3和总FoxO3的胞浆表达增强，在静止和生长条件下，Ad-Smad3共同感染会降低磷酸化FoxO3和总FoxO3的表达；Ad-FoxO3诱导泛素连接酶MuRF-1的表达和活性，与伴随的Ad-Smad3 OE相反；Smad3/FoxO3联合OE逆转了单一Smad3的促生长作用和单一FoxO3的细胞抑制作用。从这些观察中得出的一个主要结论是FoxO3能够逆转ASM细胞中Smad3促进生长的作用。其他研究结果支持Smad3对foxo3诱导的细胞停滞的相互拮抗作用，这些作用依赖于离散磷酸化状态和细胞定位，并涉及MuRF-1对ASM细胞生长的控制。最后，结果显示FoxO3能够使Smad3诱导的ASM细胞生长正常化，这在很大程度上支持了我们的假设，总体结果为Smad3和/或FoxO3作为心血管疾病中ASM异常生长的潜在治疗靶点提供了证据。
Transition of arterial smooth muscle (ASM) from a quiescent, contractile state to a growth-promoting state is a hallmark of cardiovascular disease (CVD), a leading cause of death and disability in the United States and worldwide. While many individual signals have been identified as important mechanisms in this phenotypic conversion, the combined impact of the transcription factors Smad3 and FoxO3 in ASM growth is not known. The purpose of this study was to determine that a coordinated, phosphorylation-specific relationship exists between Smad3 and FoxO3 in the control of ASM cell growth. Using a rat in vivo arterial injury model and rat primary ASM cell lysates and fractions, validated low and high serum in vitro models of respective quiescent and growth states, and adenoviral (Ad-) gene delivery for overexpression (OE) of individual and combined Smad3 and/or FoxO3, we hypothesized that FoxO3 can moderate Smad3-induced ASM cell growth. Key findings revealed unique cellular distribution of Smad3 and FoxO3 under growth conditions, with induction of both nuclear and cytosolic Smad3 yet primarily cytosolic FoxO3; Ad-Smad3 OE leading to cytosolic and nuclear expression of phosphorylated and total Smad3, with almost complete reversal of each with Ad-FoxO3 co-infection in quiescent and growth conditions; Ad-FoxO3 OE leading to enhanced cytosolic expression of phosphorylated and total FoxO3, both reduced with Ad-Smad3 co-infection in quiescent and growth conditions; Ad-FoxO3 inducing expression and activity of the ubiquitin ligase MuRF-1, which was reversed with concomitant Ad-Smad3 OE; and combined Smad3/FoxO3 OE reversing both the pro-growth impact of singular Smad3 and the cytostatic impact of singular FoxO3. A primary takeaway from these observations is the capacity of FoxO3 to reverse growth-promoting effects of Smad3 in ASM cells. Additional findings lend support for reciprocal antagonism of Smad3 on FoxO3-induced cytostasis, and these effects are dependent upon discrete phosphorylation states and cellular localization and involve MuRF-1 in the control of ASM cell growth. Lastly, results showing capacity of FoxO3 to normalize Smad3-induced ASM cell growth largely support our hypothesis, and overall findings provide evidence for utility of Smad3 and/or FoxO3 as potential therapeutic targets against abnormal ASM growth in the context of CVD.
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影响因子：
9.8
作者：
Davis, Patrick R.;Miller, Spencer G.;Brault, Jeffrey J.
通讯作者：
Brault, Jeffrey J.
DOI：
10.1073/pnas.0605333103
发表时间：
2006-08-22
影响因子：
11.1
作者：
Gomis, Roger R.;Alarcon, Claudio;Massague, Joan
通讯作者：
Massague, Joan
影响因子：
4.8
作者：
Abid, MR;Yano, K;Aird, WC
通讯作者：
Aird, WC
影响因子：
4
作者：
Stone JD;Narine A;Tulis DA
通讯作者：
Tulis DA
影响因子：
4.7
作者：
Koganti P;Levy-Cohen G;Blank M
通讯作者：
Blank M