Opposing Actions of AKT (Protein Kinase B) Isoforms in Vascular Smooth Muscle Injury and Therapeutic Response.
Opposing Actions of AKT (Protein Kinase B) Isoforms in Vascular Smooth Muscle Injury and Therapeutic Response.
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DOI：
10.1161/atvbaha.117.310053
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发表时间：
2017-12
期刊：
影响因子：
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通讯作者：
Martin KA
中科院分区：
文献类型：
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作者：
Jin Y;Xie Y;Ostriker AC;Zhang X;Liu R;Lee MY;Leslie KL;Tang W;Du J;Lee SH;Wang Y;Sessa WC;Hwa J;Yu J;Martin KA
mTORC1抑制剂药物洗脱支架在预防冠状动脉血运重建术后的内膜增生方面非常有效，但副作用限制了对全身性血管疾病的应用。了解其作用机制可能会带来新的治疗策略。我们已经表明，雷帕霉素促进血管平滑肌细胞（SMC）分化在体外akt2依赖的方式。本研究探讨AKT亚型在内膜增生中的作用。我们发现，与对照小鼠相比，种系或平滑肌特异性Akt2缺失在动脉剥脱损伤后导致更严重的内膜增生。相反，平滑肌特异性Akt1基因敲除可阻止内膜增生，而种系Akt1基因缺失可导致严重血栓形成。值得注意的是，雷帕霉素在野生型小鼠中阻止了内膜增生，但在Akt2基因敲除中没有治疗效果。我们发现AKT1和AKT2亚型在体外SMC增殖、迁移、分化和雷帕霉素反应中的相反作用。机制上，雷帕霉素诱导心肌mRNA表达。这是通过AKT2磷酸化和FOXO4的核排斥介导的，抑制其与心肌启动子的结合。我们的数据揭示了AKT亚型在SMC重塑中的相反作用。AKT2是雷帕霉素治疗性抑制内膜增生所必需的，可能部分是通过AKT2特异性调节心肌素（心肌素）通过FOXO4介导的。由于AKT2信号在糖尿病中受损，这项工作对雷帕霉素治疗具有重要意义，特别是对糖尿病患者。
Drug-eluting stent delivery of mTORC1 inhibitors is highly effective in preventing intimal hyperplasia following coronary revascularization, but adverse effects limit utility for systemic vascular disease. Understanding the mechanism of action may lead to new treatment strategies. We have shown that rapamycin promotes vascular smooth muscle cell (SMC) differentiation in an AKT2-dependent manner in vitro. Here we investigate the roles of AKT isoforms in intimal hyperplasia. We found that germline or smooth muscle-specific deletion of Akt2 resulted in more severe intimal hyperplasia compared to control mice after arterial denudation injury. Conversely, smooth muscle-specific Akt1 knockout prevented intimal hyperplasia, while germline Akt1 deletion caused severe thrombosis. Notably, rapamycin prevented intimal hyperplasia in wild type mice but had no therapeutic benefit in Akt2 knockouts. We identified opposing roles for AKT1 and AKT2 isoforms in SMC proliferation, migration, differentiation, and rapamycin response in vitro. Mechanistically, rapamycin induced MYOCD mRNA expression. This was mediated by AKT2 phosphorylation and nuclear exclusion of FOXO4, inhibiting its binding to the MYOCD promoter. Our data reveal opposing roles for AKT isoforms in SMC remodeling. AKT2 is required for rapamycin’s therapeutic inhibition of intimal hyperplasia, likely mediated in part through AKT2-specific regulation of myocardin (MYOCD) via FOXO4. Because AKT2 signaling is impaired in diabetes, this work has important implications for rapamycin therapy, particularly in diabetic patients.