Secreted Klotho Attenuates Inflammation-Associated Aortic Valve Fibrosis in Senescence-Accelerated Mice P1.
Secreted Klotho Attenuates Inflammation-Associated Aortic Valve Fibrosis in Senescence-Accelerated Mice P1.
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DOI：
10.1161/hypertensionaha.117.10560
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发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
Sun Z
中科院分区：
文献类型：
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作者：
Chen J;Fan J;Wang S;Sun Z
衰老加速小鼠P1（SAMP 1）是一种衰老模型，其特征在于寿命缩短和衰老的早期迹象。Klotho是一个衰老抑制基因。本研究的目的是研究分泌型klotho（Skl）基因的体内表达是否减轻SAMP 1小鼠主动脉瓣纤维化。使用SAMP 1小鼠和年龄匹配（AKR/J）对照小鼠。SAMP 1小鼠主动脉瓣出现明显的纤维化，即纤维化主动脉瓣病（FAVD）。SAMP 1小鼠血清Sk 1水平显著降低。MCP-1、ICAM-1、F4/80和CD 68在SAMP 1小鼠的主动脉瓣中的表达增加，表明炎症。SAMP 1小鼠主动脉瓣中也发现α-SMA（肌成纤维细胞标志物）、TGFβ-1和硬化轴（胶原合成的转录因子）的表达增加，表明加速老化与肌成纤维细胞转变和胶原基因激活有关。我们构建了携带小鼠Sk 1 cDNA的腺相关病毒2（AAV 2）（AAV 2-Sk 1），用于体内表达Sk 1。SK 1基因转染能有效提高SAMP 1小鼠血清SK 1水平。Skl基因递送抑制SAMP 1小鼠主动脉瓣中的炎症和肌纤维母细胞转化，并减弱FAVD。得出结论，SAMP 1小鼠中衰老相关的FAVD与血清klotho降低相关，导致炎症，包括巨噬细胞浸润和主动脉瓣中TGFβ-1/Scleraxis驱动的肌成纤维细胞分化。通过AAV 2-Skl恢复血清Skl水平有效地抑制炎症和肌纤维母细胞转化并减弱主动脉瓣纤维化。Sk 1可能是FAVD潜在的治疗靶点。
Senescence accelerated mice P1 (SAMP1) is an aging model characterized by shortened lifespan and early signs of senescence. Klotho is an aging-suppressor gene. The purpose of this study is to investigate whether in vivo expression of secreted klotho (Skl) gene attenuates aortic valve fibrosis in SAMP1 mice. SAMP1 mice and age-matched (AKR/J) control mice were used. SAMP1 mice developed obvious fibrosis in aortic valves, namely fibrotic aortic valve disease (FAVD). Serum level of Skl was decreased drastically in SAMP1 mice. Expression of MCP-1, ICAM-1, F4/80, and CD68 was increased in aortic valves of SAMP1 mice, indicating inflammation. An increase in expression of α-SMA (myofibroblast marker), TGFβ-1 and scleraxis (a transcription factor of collagen synthesis) was also found in aortic valves of SAMP1 mice, suggesting that accelerated aging is associated with myofiborblast transition and collagen gene activation. We constructed adeno-associated virus 2 (AAV2) carrying mouse Skl cDNA (AAV2-Skl) for in vivo expression of Skl. Skl gene delivery effectively increased serum Skl of SAMP1 mice to the control level. Skl gene delivery inhibited inflammation and myofibroblastic transition in aortic valves and attenuated FAVD in SAMP1 mice. It is concluded that senescence-related FAVD in SAMP1 mice is associated with a decrease in serum klotho leading to inflammation including macrophage infiltration and TGFβ-1/Scleraxis-driven myofibroblast differentiation in aortic valves. Restoration of serum Skl levels by AAV2-Skl effectively suppresses inflammation and myofibroblastic transition and attenuates aortic valve fibrosis. Skl may be a potential therapeutic target for FAVD.