Inhibitory effects of growth differentiation factor 11 on autophagy deficiency-induced dedifferentiation of arterial smooth muscle cells.
Inhibitory effects of growth differentiation factor 11 on autophagy deficiency-induced dedifferentiation of arterial smooth muscle cells.
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DOI：
10.1152/ajpheart.00342.2018
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发表时间：
2019-02
期刊：
影响因子：
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通讯作者：
Xinxu Yuan;O. Bhat;H. Lohner;Ningjun Li;Yang Zhang;Pin-Lan Li
中科院分区：
文献类型：
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作者：
Xinxu Yuan;O. Bhat;H. Lohner;Ningjun Li;Yang Zhang;Pin-Lan Li
据报道，生长分化因子（GDF）11可逆转小鼠年龄相关的心脏肥大，并引起心肌细胞的年轻再生。本研究试图验证一个假设，即GDF 11抵消病理去分化的小鼠颈动脉平滑肌细胞（CASMCs）由于缺乏自噬。通过实时定量RT-PCR和Western blot分析，发现外源性给予GDF 11促进CASMC分化，增加各种分化标志物（α-平滑肌肌动蛋白、肌生成素、肌生成分化和肌球蛋白重链）的表达，以及减少去分化标志物（波形蛋白和增殖细胞核抗原）的表达。GDF 11基因通过抑制素A（TSA）或CRISPR-cas9激活质粒的上调也刺激了CASMC的分化。GDF 11或TSA处理阻断7-酮胆固醇诱导的CASMC去分化和自噬体积累以及溶酶体抑制剂巴菲霉素诱导的去分化和自噬体积累。此外，在来自缺乏CD 38基因的小鼠的CASMC（CASMC中的自噬缺陷模型）中，GDF 11也抑制其向去分化状态的表型转变。相应地，TSA处理显示在部分结扎的小鼠颈动脉中降低GDF 11表达并逆转CASMC去分化。TSA对CASMC去分化的抑制作用伴随着动脉壁中自噬体积累的减少，这伴随着部分结扎的颈动脉中新生内膜形成的减弱。我们的结论是，GDF 11促进CASMC分化，并防止这些细胞的表型转变诱导自噬体积累在不同的病理刺激，如西方饮食，溶酶体功能缺陷，炎症。本研究表明，生长分化因子（GDF）11促进颈动脉平滑肌细胞的自噬和随后的分化。GDF 11的上调在不同病理条件下抵消去分化。这些发现为GDF 11在抵抗动脉硬化疾病中的调节作用提供了新的见解，并且还表明GDF 11的激活或诱导可能是治疗或预防这些疾病的新的治疗策略。
Growth differentiation factor (GDF)11 has been reported to reverse age-related cardiac hypertrophy in mice and cause youthful regeneration of cardiomyocytes. The present study attempted to test a hypothesis that GDF11 counteracts the pathologic dedifferentiation of mouse carotid arterial smooth muscle cells (CASMCs) due to deficient autophagy. By real-time RT-PCR and Western blot analysis, exogenously administrated GDF11 was found to promote CASMC differentiation with increased expression of various differentiation markers (α-smooth muscle actin, myogenin, myogenic differentiation, and myosin heavy chain) as well as decreased expression of dedifferentiation markers (vimentin and proliferating cell nuclear antigen). Upregulation of the GDF11 gene by trichostatin A (TSA) or CRISPR-cas9 activating plasmids also stimulated the differentiation of CASMCs. Either GDF11 or TSA treatment blocked 7-ketocholesterol-induced CASMC dedifferentiation and autophagosome accumulation as well as lysosome inhibitor bafilomycin-induced dedifferentiation and autophagosome accumulation. Moreover, in CASMCs from mice lacking the CD38 gene, an autophagy deficiency model in CASMCs, GDF11 also inhibited its phenotypic transition to dedifferentiation status. Correspondingly, TSA treatment was shown to decrease GDF11 expression and reverse CASMC dedifferentiation in the partial ligated carotid artery of mice. The inhibitory effects of TSA on dedifferentiation of CASMCs were accompanied by reduced autophagosome accumulation in the arterial wall, which was accompanied by attenuated neointima formation in partial ligated carotid arteries. We concluded that GDF11 promotes CASMC differentiation and prevents the phenotypic transition of these cells induced by autophagosome accumulation during different pathological stimulations, such as Western diet, lysosome function deficiency, and inflammation. NEW & NOTEWORTHY The present study demonstrates that growth differentiation factor (GDF)11 promotes autophagy and subsequent differentiation in carotid arterial smooth muscle cells. Upregulation of GDF11 counteracts dedifferentiation under different pathological conditions. These findings provide novel insights into the regulatory role of GDF11 in the counteracting of sclerotic arterial diseases and also suggest that activation or induction of GDF11 may be a new therapeutic strategy for the treatment or prevention of these diseases.