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Potential role of full-length and nonfull-length progranulin in affecting aortic valve calcification.
Journal of Molecular and Cellular Cardiology ( IF 4.9 ) Pub Date : 2020-04-02 , DOI: 10.1016/j.yjmcc.2020.03.012 Gaigai Huang 1 , Liqin An 1 , Mengtian Fan 1 , Menghao Zhang 1 , Bin Chen 1 , Mengying Zhu 1 , Jinghong Wu 1 , Yan Liu 1 , Yue Wang 1 , Qin Huang 1 , Qiong Shi 1 , Yaguang Weng 1
Journal of Molecular and Cellular Cardiology ( IF 4.9 ) Pub Date : 2020-04-02 , DOI: 10.1016/j.yjmcc.2020.03.012 Gaigai Huang 1 , Liqin An 1 , Mengtian Fan 1 , Menghao Zhang 1 , Bin Chen 1 , Mengying Zhu 1 , Jinghong Wu 1 , Yan Liu 1 , Yue Wang 1 , Qin Huang 1 , Qiong Shi 1 , Yaguang Weng 1
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Inflammation is implicated in the pathogenesis of calcific aortic valve disease (CAVD) which is a major contributor to cardiovascular mortality and lacks non-surgical treatment. The progranulin (PGRN) is an important immunomodulatory factor in a variety of inflammatory diseases, including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease and pneumonia. However, its role in calcification of aortic valve remains unknown. We firstly found that PGRN was increased in calcified human aortic valve (AV) tissues. Interestingly, in addition to full-length PGRN (68KD), a much stronger band of approximately 45 KD was also significantly increased. The band of 45 KD (45-GRN), was present in wild type (WT) mouse MEFs and AV but absent in grn-/-MEFs, indicating that it was a specific degradation product derived from PGRN. 45-GRN was upregulated whereas PGRN was reduced in human valve interstitial cells (hVICs) under calcifying conditions which is induced by osteogenic medium (OM). In primary porcine VICs (pVICs), PGRN downregulated TNF-α and α-SMA which was accompanied by downregulation of RUNX2, OPN, OCN, alkaline phosphatase activity and calcium deposition, effects pointing to reduced inflammation, myofibroblastic and osteoblastic transition under calcifying conditions. We overexpressed a mimic of 45-GRN which contains p-G-F-B-A-C in pVICs. However, 45-GRN overexpression promoted OM-induced calcification through activating the Smad1/5/8, NF-κB and AKT signaling pathways. Inhibition of the three signaling pathways suppressed 45-GRN's effect on VICs phenotype transition. 45-GRN promoted TNF-α and expressed converse pathogenic signatures with PGRN during TNF-α stimulation. Collectively, this study provides new insight into the pathogenesis of CAVD, indicating that PGRN is a stratagem in mitigating valve fibrosis/osteoblastic differentiation, and also presenting 45-GRN as a potential target for the treatment of CAVD.
中文翻译：
全长和非全长颗粒蛋白原在影响主动脉瓣钙化中的潜在作用。
炎症与钙化主动脉瓣疾病（CAVD）的发病机理有关，钙化主动脉瓣疾病是导致心血管疾病死亡的主要原因，并且缺乏非手术治疗。前颗粒蛋白（PGRN）是多种炎性疾病（包括类风湿性关节炎，骨关节炎，炎性肠病和肺炎）中的重要免疫调节因子。然而，其在主动脉瓣钙化中的作用仍然未知。我们首先发现在钙化的人主动脉瓣（AV）组织中PGRN升高。有趣的是，除了全长PGRN（68KD）外，大约45 KD的强度也大大提高了。45 KD（45-GRN）的条带存在于野生型（WT）小鼠MEF和AV中，但在grn-/-MEF中不存在，表明它是源自PGRN的特定降解产物。在成骨性培养基（OM）诱导的钙化条件下，人瓣膜间质细胞（hVIC）中45-GRN上调，而PGRN降低。在初级猪VIC（pVIC）中，PGRN下调TNF-α和α-SMA，同时下调RUNX2，OPN，OCN，碱性磷酸酶活性和钙沉积，其作用表明在钙化条件下炎症减少，成纤维细胞和成骨细胞转变减少。我们在pVIC中过表达了45-GRN的模拟物，其中包含pGFBAC。然而，45-GRN的过表达通过激活Smad1 / 5/8，NF-κB和AKT信号通路来促进OM诱导的钙化。抑制这三个信号通路抑制了45-GRN对VICs表型转变的影响。45-GRN促进TNF-α并在TNF-α刺激过程中与PGRN表达相反的病原体特征。总的来说，这项研究为CAVD的发病机理提供了新的见解，表明PGRN是缓解瓣膜纤维化/成骨细胞分化的战略，并且还提出了45-GRN作为CAVD治疗的潜在靶标。
更新日期：2020-04-03
中文翻译：
全长和非全长颗粒蛋白原在影响主动脉瓣钙化中的潜在作用。
炎症与钙化主动脉瓣疾病（CAVD）的发病机理有关，钙化主动脉瓣疾病是导致心血管疾病死亡的主要原因，并且缺乏非手术治疗。前颗粒蛋白（PGRN）是多种炎性疾病（包括类风湿性关节炎，骨关节炎，炎性肠病和肺炎）中的重要免疫调节因子。然而，其在主动脉瓣钙化中的作用仍然未知。我们首先发现在钙化的人主动脉瓣（AV）组织中PGRN升高。有趣的是，除了全长PGRN（68KD）外，大约45 KD的强度也大大提高了。45 KD（45-GRN）的条带存在于野生型（WT）小鼠MEF和AV中，但在grn-/-MEF中不存在，表明它是源自PGRN的特定降解产物。在成骨性培养基（OM）诱导的钙化条件下，人瓣膜间质细胞（hVIC）中45-GRN上调，而PGRN降低。在初级猪VIC（pVIC）中，PGRN下调TNF-α和α-SMA，同时下调RUNX2，OPN，OCN，碱性磷酸酶活性和钙沉积，其作用表明在钙化条件下炎症减少，成纤维细胞和成骨细胞转变减少。我们在pVIC中过表达了45-GRN的模拟物，其中包含pGFBAC。然而，45-GRN的过表达通过激活Smad1 / 5/8，NF-κB和AKT信号通路来促进OM诱导的钙化。抑制这三个信号通路抑制了45-GRN对VICs表型转变的影响。45-GRN促进TNF-α并在TNF-α刺激过程中与PGRN表达相反的病原体特征。总的来说，这项研究为CAVD的发病机理提供了新的见解，表明PGRN是缓解瓣膜纤维化/成骨细胞分化的战略，并且还提出了45-GRN作为CAVD治疗的潜在靶标。
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