Salt-Inducible Kinase 3 Promotes Vascular Smooth Muscle Cell Proliferation and Arterial Restenosis by Regulating AKT and PKA-CREB Signaling.
Salt-Inducible Kinase 3 Promotes Vascular Smooth Muscle Cell Proliferation and Arterial Restenosis by Regulating AKT and PKA-CREB Signaling.
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DOI：
10.1161/atvbaha.121.316219
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Guzman RJ
中科院分区：
文献类型：
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作者：
Cai Y;Wang XL;Lu J;Lin X;Dong J;Guzman RJ
动脉再狭窄是血管内手术后动脉的病理性狭窄，是导致患者出现复发性闭塞症状的不良事件。血管成形术后，血管平滑肌细胞（SMC）改变其表型，迁移和增殖，导致新生内膜形成，这是动脉再狭窄的标志。盐诱导激酶（Salt-inducible kinases，SIKs）是腺苷酸活化蛋白激酶家族的一个亚家族，在肝脏脂肪生成和葡萄糖代谢等代谢性疾病中发挥重要作用。然而，它们在血管病理性重塑中的作用尚未被探索。本研究旨在了解SIK 3在血管平滑肌细胞迁移、增殖和新生内膜形成中的作用和调控。我们观察到，收缩的主动脉SMC中的SIK 3表达较低，但在增殖的SMC中的SIK 3表达较高。在体外生长培养基和体内新生内膜病变中也高度诱导。SIKs的失活可显著抑制血管平滑肌细胞增殖，并上调p21 CIP 1和p27 KIP 1。SIK抑制也抑制SMC迁移和调制肌动蛋白聚合。重要的是，我们发现在股动脉钢丝损伤模型中，抑制SIKs可减少新生内膜形成和血管炎症。在机制研究中，我们证明了SIKs的失活主要通过下调AKT和PKA-CREB信号转导抑制SMC增殖。CRTC 3信号传导可能有助于SIK失活介导的抗增殖作用。这些发现表明，SIK 3可能在调节SMC增殖、迁移和动脉再狭窄中发挥关键作用。本研究提供了对抑制SIK作为治疗外周动脉疾病患者再狭窄的潜在治疗策略的见解。
Arterial restenosis is the pathological narrowing of arteries after endovascular procedures, and it is an adverse event that causes patients to experience recurrent occlusive symptoms. Following angioplasty, vascular smooth muscle cells (SMCs) change their phenotype, migrate, and proliferate, resulting in neointima formation, a hallmark of arterial restenosis. Salt-inducible kinases (SIKs) are a subfamily of the AMP-activated protein kinase family that play a critical role in metabolic diseases including hepatic lipogenesis and glucose metabolism. Their role in vascular pathological remodeling, however, has not been explored. In this study, we aimed to understand the role and regulation of SIK3 in vascular SMC migration, proliferation, and neointima formation. We observed that SIK3 expression was low in contractile aortic SMCs but high in proliferating SMCs. It was also highly induced by growth medium in vitro and in neointimal lesions in vivo. Inactivation of SIKs significantly attenuated vascular SMC proliferation and up-regulated p21CIP1 and p27KIP1. SIK inhibition also suppressed SMC migration and modulated actin polymerization. Importantly, we found that inhibition of SIKs reduced neointima formation and vascular inflammation in a femoral artery wire injury model. In mechanistic studies, we demonstrated that inactivation of SIKs mainly suppressed SMC proliferation by down-regulating AKT and PKA-CREB signaling. CRTC3 signaling likely contributed to SIK inactivation-mediated anti-proliferative effects. These findings suggest that SIK3 may play a critical role in regulating SMC proliferation, migration, and arterial restenosis. This study provides insights into SIK inhibition as a potential therapeutic strategy for treating restenosis in patients with peripheral arterial disease.