miR-34a Promotes Vascular Smooth Muscle Cell Calcification by Downregulating SIRT1 (Sirtuin 1) and Axl (AXL Receptor Tyrosine Kinase)
miR-34a Promotes Vascular Smooth Muscle Cell Calcification by Downregulating SIRT1 (Sirtuin 1) and Axl (AXL Receptor Tyrosine Kinase)
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DOI：
10.1161/atvbaha.118.311298
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发表时间：
2018-09-01
影响因子：
8.7
通讯作者：
Raucci, Angela
中科院分区：
文献类型：
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作者：
Badi, Ileana;Mancinelli, Luigi;Raucci, Angela
目的血管钙化（VC）具有年龄依赖性，是心血管和全因死亡的危险因素。VC涉及衰老诱导的血管平滑肌细胞（SMC）向骨软骨形成谱系的转分化，导致动脉壁矿化。miR-34 a在老年人中随着年龄的增长而增加，并通过调节其靶点SIRT 1（sirtuin 1）诱导血管SMC衰老。在这项研究中，我们的目的是调查是否miR-34 a调节VC。方法和结果我们发现，miR-34 a和Runx 2（Runt相关转录因子2）的表达相关的年轻和老年小鼠。Mir 34 a（+/+）和Mir 34 a（-/-）小鼠用维生素D治疗，钙定量显示Mir 34 a缺乏减少软组织和主动脉中膜钙化，并上调VC Sox 9（SRY [性别决定区Y]-框9）和Runx 2以及衰老p16和p21标记物。在该模型中，miR-34 a上调是短暂的，并且先于主动脉矿化。与Mir 34 a（+/+）细胞相比，Mir 34 a（-/-）SMCs不太容易经历衰老，并且在成骨条件下沉积较少的钙。此外，与Mir 34 a（+/+）SMC不同，已知的VC抑制剂SIRT 1和Axl（AXL受体酪氨酸激酶）在钙化的Mir 34 a（-/-）SMC中仅部分下调。引人注目的是，在人主动脉SMC中组成性miR-34 a过表达至衰老样水平增加了钙沉积，并增强了钙化期间Axl和SIRT 1的降低。值得注意的是，我们还发现，miR-34 a直接降低Axl在人主动脉SMC的表达，并恢复其水平部分挽救miR-34 a依赖的growth arrest.Conclusions miR-34 a通过抑制细胞增殖和诱导衰老，分别通过直接Axl和SIRT 1下调，促进VC通过血管SMC矿化。该miRNA可能成为治疗VC的良好靶点。
Objective Vascular calcification (VC) is age dependent and a risk factor for cardiovascular and all-cause mortality. VC involves the senescence-induced transdifferentiation of vascular smooth muscle cells (SMCs) toward an osteochondrogenic lineage resulting in arterial wall mineralization. miR-34a increases with age in aortas and induces vascular SMC senescence through the modulation of its target SIRT1 (sirtuin 1). In this study, we aimed to investigate whether miR-34a regulates VC.Approach and Results We found that miR-34a and Runx2 (Runt-related transcription factor 2) expression correlates in young and old mice. Mir34a(+/+) and Mir34a(-/-) mice were treated with vitamin D, and calcium quantification revealed that Mir34a deficiency reduces soft tissue and aorta medial calcification and the upregulation of the VC Sox9 (SRY [sex-determining region Y]-box 9) and Runx2 and the senescence p16 and p21 markers. In this model, miR-34a upregulation was transient and preceded aorta mineralization. Mir34a(-/-) SMCs were less prone to undergo senescence and under osteogenic conditions deposited less calcium compared with Mir34a(+/+) cells. Furthermore, unlike in Mir34a(+/+) SMC, the known VC inhibitors SIRT1 and Axl (AXL receptor tyrosine kinase) were only partially downregulated in calcifying Mir34a(-/-) SMC. Strikingly, constitutive miR-34a overexpression to senescence-like levels in human aortic SMCs increased calcium deposition and enhanced Axl and SIRT1 decrease during calcification. Notably, we also showed that miR-34a directly decreased Axl expression in human aortic SMC, and restoration of its levels partially rescued miR-34a-dependent growth arrest.Conclusions miR-34a promotes VC via vascular SMC mineralization by inhibiting cell proliferation and inducing senescence through direct Axl and SIRT1 downregulation, respectively. This miRNA could be a good therapeutic target for the treatment of VC.