The effect of HMGA1 in LPS-induced Myocardial Inflammation
The effect of HMGA1 in LPS-induced Myocardial Inflammation
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DOI：
10.7150/ijbs.39947
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发表时间：
2020-01-01
影响因子：
9.2
通讯作者：
Tang, Qi-Zhu
中科院分区：
文献类型：
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作者：
Cai, Zhu-Lan;Shen, Bo;Tang, Qi-Zhu
目的：高迁移率族A1（High Mobility Group A1，HMGA 1）蛋白作为基因转录和染色质重塑的动态调节因子，在许多心血管疾病的病理过程中发挥重要作用。然而，HMGA 1在脓毒症诱导的心肌病（SIC）中的确切作用仍然不清楚。本研究旨在阐明HMGA 1参与SIC的作用。方法和结果：采用腺相关病毒系统，通过心肌内注射，获得心肌细胞特异性HMGA 1过表达。腹腔注射脂多糖（LPS）6 h建立SIC小鼠模型。用LPS刺激H9 c2大鼠心肌细胞12 h。HMGA 1的表达在小鼠炎症心脏以及LPS刺激的H9 c2心肌细胞中上调。在体内和体外实验中，过表达HMGA 1的大鼠在LPS处理后，心功能不全加重，心肌炎症加重，细胞凋亡增加。有趣的是，H9 c2心肌细胞中HMGA 1的敲低减弱了LPS诱导的心肌细胞炎症，但加重了细胞凋亡。从机制上讲，我们发现HMGA 1的过表达诱导环氧合酶-2（考克斯-2）的表达增加。考克斯-2抑制剂可减轻HMGA 1过表达的H9 c2心肌细胞的炎症和凋亡，而HMGA 1敲低可诱导信号转导和转录激活因子3（STAT 3）表达的减少。结论：HMGA 1过表达可通过上调考克斯-2的表达而加重心肌细胞的炎症反应和凋亡，而HMGA 1表达沉默可通过下调STAT 3的表达而减轻炎症反应，但可促进心肌细胞凋亡。
Aims: The High Mobility Group A1 (HMGA1) proteins, serving as a dynamic regulator of gene transcription and chromatin remodeling, play an influential part in the pathological process of a large number of cardiovascular diseases. However, the precise role of HMGA1 in sepsis induced cardiomyopathy (SIC) remains unintelligible. This research was designed to illustrate the effect of HMGA1 involved in SIC.Methods and Results: Cardiomyocyte-specific HMGA1 overexpression was obtained using an adeno-associated virus system with intramyocardial injection in mice heart. The model of SIC in mice was constructed via intraperitoneal injection of lipopolysaccharide (LPS) for 6h. H9c2 rat cardiomyocytes was stimulated with LPS for 12h. HMGA1 expression was upregulated in murine inflammatory hearts as well as LPS stimulated H9c2 cardiomyocytes. HMGA1-overexpressing exhibited aggravated cardiac dysfunction, cardiac inflammation as well as cells apoptosis following LPS treatment both in vivo and in vitro experiment. Interestingly, HMGA1 knockdown in H9c2 cardiomyocytes attenuated LPS-induced cardiomyocyte inflammation, but aggravated cell apoptosis. Mechanistically, we found that overexpression of HMGA1 induced increased expression of cyclooxygenase-2 (COX-2). COX-2 inhibitor alleviated the aggravation of inflammation and apoptosis in HMGA1 overexpressed H9c2 cardiomyocytes whereas HMGA1 knockdown induced a reduction in signal transducer and activators of transcription 3 (STAT3) expression. STAT3 agonist reversed HMGA1 silence induced anti-inflammatory effects, while ameliorated cell apoptosis induced by LPS.Conclusion: In conclusion, our results suggest that overexpression of HMGA1 aggravated cardiomyocytes inflammation and apoptosis by up-regulating COX-2 expression, while silence of HMGA1 expression attenuated inflammation but aggregated cell apoptosis via down-regulation of STAT3.