Myeloid CCN3 protects against aortic valve calcification.
Myeloid CCN3 protects against aortic valve calcification.
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DOI：
10.1186/s12964-022-01020-0
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发表时间：
2023-01-20
影响因子：
8.4
通讯作者：
Lin, Zhiyong
中科院分区：
文献类型：
--
作者：
Tu, Peinan;Xu, Qian;Zhou, Xianming;Villa-Roel, Nicolas;Kumar, Sandeep;Dong, Nianguo;Jo, Hanjoong;Ou, Caiwen;Lin, Zhiyong
细胞通讯网络因子3（CCN 3）参与成骨细胞分化的调控。然而，尚不清楚CCN 3是否可以调节瓣膜钙化。虽然巨噬细胞已被证明可以调节瓣膜钙化，但这一过程的分子和细胞机制仍知之甚少。在本研究中，我们研究了巨噬细胞源性CCN 3在钙化性主动脉瓣疾病进展中的作用。 对CCN 3的骨髓特异性敲除（Mye-CCN 3-KO）和对照小鼠进行编码突变体mPCSK 9的AAV（rAAV 8/D377 Y-mPCSK 9）的单尾静脉内注射以诱导高脂血症。然后给注射AAV的小鼠喂食高脂肪饮食40周。在高脂饲料喂养结束时，收获组织并进行组织学和病理学分析。体外培养Mye-CCN 3-KO小鼠和对照小鼠骨髓源性巨噬细胞（BMDM），通过实时荧光定量PCR和Western blotting检测BMDM中骨形态发生蛋白信号相关基因的表达。将BMDM条件培养液与人工诱导钙化的人心瓣膜间质细胞共培养，通过Western blotting和茜素红染色检测BMDM条件培养液对人心瓣膜间质细胞的影响。超声心动图显示雄性和雌性Mye-CCN 3-KO小鼠均显示主动脉瓣功能受损，伴有瓣膜厚度加重和心功能不全。在组织学上，茜素红染色显示，与对照组相比，Mye-CCN 3-KO小鼠的主动脉瓣钙化显著增加。在体外，CCN 3缺乏增强骨髓源性巨噬细胞的BMP 2产生和分泌。此外，用来自CCN 3缺陷型BMDM的条件培养基培养的人瓣膜间质细胞导致过度的促钙化基因表达和随之而来的钙化。我们的数据揭示了髓样CCN 3在调节主动脉瓣钙化中的新作用。巨噬细胞源性CCN 3对巨噬细胞BMP 2产生和分泌的调节可能是其抗钙化作用的重要机制之一。视频摘要在线版本包含补充材料，可通过10. 1186/s12964-022-01020-0获取。
Cellular communication network factor 3 (CCN3) has been implicated in the regulation of osteoblast differentiation. However, it is not known if CCN3 can regulate valvular calcification. While macrophages have been shown to regulate valvular calcification, the molecular and cellular mechanisms of this process remain poorly understood. In the present study, we investigated the role of macrophage-derived CCN3 in the progression of calcific aortic valve disease. Myeloid-specific knockout of CCN3 (Mye-CCN3-KO) and control mice were subjected to a single tail intravenous injection of AAV encoding mutant mPCSK9 (rAAV8/D377Y-mPCSK9) to induce hyperlipidemia. AAV-injected mice were then fed a high fat diet for 40 weeks. At the conclusion of high fat diet feeding, tissues were harvested and subjected to histologic and pathologic analyses. In vitro, bone marrow-derived macrophages (BMDM) were obtained from Mye-CCN3-KO and control mice and the expression of bone morphogenic protein signaling related gene were verified via quantitative real-time PCR and Western blotting. The BMDM conditioned medium was cocultured with human valvular intersititial cells which was artificially induced calcification to test the effect of the conditioned medium via Western blotting and Alizarin red staining. Echocardiography revealed that both male and female Mye-CCN3-KO mice displayed compromised aortic valvular function accompanied by exacerbated valve thickness and cardiac dysfunction. Histologically, Alizarin-Red staining revealed a marked increase in aortic valve calcification in Mye-CCN3-KO mice when compared to the controls. In vitro, CCN3 deficiency augmented BMP2 production and secretion from bone marrow-derived macrophages. In addition, human valvular interstitial cells cultured with conditioned media from CCN3-deficient BMDMs resulted in exaggerated pro-calcifying gene expression and the consequent calcification. Our data uncovered a novel role of myeloid CCN3 in the regulation of aortic valve calcification. Modulation of BMP2 production and secretion in macrophages might serve as a key mechanism for macrophage-derived CCN3’s anti-calcification function in the development of CAVD. Video Abstract The online version contains supplementary material available at 10.1186/s12964-022-01020-0.
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4.5
作者：
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作者：
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影响因子：
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作者：
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