Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, RP China.
Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, RP China.
Int J Biol Sci. 2020 Mar 26;16(11):1798-1810. doi: 10.7150/ijbs.39947. eCollection 2020.
: 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. : 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 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. : 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.
高迁移率族蛋白 A1（HMGA1）作为基因转录和染色质重塑的动态调节剂，在许多心血管疾病的病理过程中发挥着重要作用。然而，HMGA1 在脓毒症性心肌病（SIC）中的确切作用尚不清楚。本研究旨在阐明 HMGA1 参与 SIC 的作用。
通过心肌内注射腺相关病毒系统在小鼠心脏中获得心肌细胞特异性 HMGA1 过表达。通过腹腔内注射脂多糖（LPS）6h 构建 SIC 小鼠模型。用 LPS 刺激 H9c2 大鼠心肌细胞 12h。HMGA1 在炎性小鼠心脏以及 LPS 刺激的 H9c2 心肌细胞中表达上调。HMGA1 过表达在 LPS 处理后体内和实验中均加剧了心脏功能障碍、心脏炎症和细胞凋亡。有趣的是，在 H9c2 心肌细胞中敲低 HMGA1 可减轻 LPS 诱导的心肌细胞炎症，但加重细胞凋亡。机制上，我们发现 HMGA1 过表达诱导环氧化酶-2（COX-2）表达增加。COX-2 抑制剂减轻了 HMGA1 过表达 H9c2 心肌细胞中炎症和凋亡的加重，而 HMGA1 敲低则导致信号转导和转录激活因子 3（STAT3）表达减少。STAT3 激动剂逆转了 HMGA1 沉默诱导的抗炎作用，同时减轻了 LPS 诱导的细胞凋亡。
综上所述，我们的研究结果表明，HMGA1 过表达通过上调 COX-2 表达加剧心肌细胞炎症和凋亡，而 HMGA1 表达沉默通过下调 STAT3 减轻炎症但加重细胞凋亡。
