SOCS调控炎症反应防治心脏瓣膜钙化机制研究

Heart valve calcification is a common clinical problem with high morbidity and mortality, and to date there are no effective drug therapy or preventive methods for it. In the past decade, an abundance of evidence have suggested that, valve calcification is not simply a passive degenerative disease, but an active pathological progress akin to atherosclerosis, including endothelial dysfunction ,lipoprotein deposition, chronic inflammation, extracellular matrix remodeling. The crucial role of chronic inflammation in valve calcification has been widely documented. Nevertheless, mechanism for chronic inflammation on valve biology is far from being fully understood..Macrophage and inflammatory cytokines constitute the main part of chronic inflammation. Depending on the microenvironment, macrophages can polarize to distinct functional phenotypes: pro-inflammatory classically activated macrophages (M1 macrophages) and anti-inflammatory alternatively activated macrophages (M2 macrophages). Recent studies demonstrate that the ratio of M1/M2 macrophages was positively correlated with the severity of coronary atherosclerosis, whereas the association between macrophage polarization and valve calcification has not been defined. Most cytokines use the so-called janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway, and this pathway also acts as a key regulator in macrophage polarization. Therefore, JAK-STAT controls the important inflammatory process. Altogether, these indicate that JAK-STAT signaling pathway may participate the pathogenesis of valve calcification..Suppressors of cytokine signaling (SOCS) proteins are target genes of JAK-STAT pathway, and they play pivotal role in negative regulation of JAK-STAT. Accumulating evidence shows that dysregulation of cytokine signaling by differential SOCS expression, especially SCOS1 and SOCS3, is involved in various inflammatory, immune and infectious diseases. SOCS were found highly expressed both in human atherosclerotic plaques and in experimental atherosclerosis. And SOCS3 knockdown exacerbate the atherosclerotic process in apoE-/- mice by increasing the size, macrophage content and chemokines expression in the lesions. All these were accompanied by STAT1/STAT3 activation. In view of the similarities between heart valve calcification and atherosclerosis, negative regulation of JAK-STAT by SOCS seems a promising intervention for alleviating valve calcificaion. .In this project, we are aiming to investigate: whether SOCS plays a pivotal role in the pathogenesis of valve calcification by regulating inflammatory reactions through JAK-STAT signaling pathway.

心脏瓣膜钙化严重危害人类健康，其发病机制目前尚不明确。本课题组前期实验及诸多研究表明：慢性炎症反应在瓣膜钙化启动和进展中起重要作用；单核巨噬细胞在不同微环境刺激下极化为不同功能表型，调控局部炎症反应；JAK-STAT信号转导是炎症因子发挥效应的共同通路，广泛参与细胞增殖、分化、凋亡及免疫调节等病理生理过程；SOCS是JAK-STAT信号通路的靶基因，通过负性调控减少炎症因子及凋亡基因等表达。鉴于此，我们推测：JAK-STAT信号通路可能参与心脏瓣膜钙化的病理过程，SOCS通过抑制JAK-STAT基因表达，影响炎症反应，干预瓣膜钙化的发生发展。本项目拟通过检测人体钙化瓣膜，构建瓣膜钙化动物和细胞模型，利用shRNA体内基因沉默技术，可控性施加干预措施，探讨SOCS调控JAK-STAT信号转导通路在瓣膜炎症反应及瓣膜钙化中的作用及分子机制，为药物防治天然或生物瓣膜钙化提供新思路。

心脏瓣膜钙化严重危害人类健康，是多种因素共同调节的主动过程，其发病机制目前尚不明确。JAK-STAT信号转导是炎症因子发挥效应的共同通路，广泛参与细胞增殖、分化、凋亡及免疫调节等病理生理过程；而SOCS是JAK-STAT信号通路的靶基因，通过负性调控减少炎症因子及凋亡基因等表达。本课题组重点研究SOCS蛋白是否参与负性调控主动脉瓣钙化，并同时研究巨噬细胞极化是否参与瓣膜钙化过程。.课题组重点对SOCS3及JAK2/STAT3通路进行深入研究后发现，SOCS3在钙化主动脉瓣膜中高表达。LPS可刺激瓣膜间质细胞（VICs）中SOCS3高表达。而SOCS3高表达可显著降低VICs成骨样分化能力，并抑制其成钙能力。SOCS3同时可以通过IL-6介导的JAK2/STAT3通路发挥其负性调控作用。基于上述结果，我们可以继续深入研究，如何更好的调节SOCS3的表达，使其可以负向调控主动脉瓣瓣膜钙化过程并减轻瓣膜钙化，抑制其成骨样变速度，控制其钙化进展。最终达到提前预防治疗主动脉瓣钙化疾病的问题。.课题组同时对巨噬细胞极化是否参与瓣膜钙化进行深入研究。单核-巨噬细胞在不同微环境刺激下极化为不同功能表型，调控局部炎症反应，并且参与瓣膜钙化全过程，其中M1型巨噬细胞及其产物可刺激瓣膜间质细胞钙化，促进瓣膜钙化的发生和发展，而M2型巨噬细胞则未表现出促钙化特性。M1型巨噬细胞在钙化瓣膜上高表达，并且取M1型巨噬细胞上清液与VICs共培养，证实其分泌细胞因子等产物可促进VICs成骨样变，增强其成钙能力。基于上述结果，可以继续深入研究调控M1型巨噬细胞极化方向，通过减少M1型巨噬细胞，达到减轻瓣膜钙化，减轻瓣膜间质细胞成骨样分化，减轻其成钙能力。最终提前干预，达到防治主动脉瓣钙化疾病的目的。

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