Data_Sheet_1_The Role of Allograft Inflammatory Factor-1 in the Effects of Experimental Diabetes on B Cell Functions in the Heart.pdf

Diabetes mellitus (DM) often causes chronic inflammation, hypertrophy, apoptosis and fibrosis in the heart and subsequently leads to myocardial remodeling, deteriorated cardiac function and heart failure. However, the etiology of the cardiac disease is unknown. Therefore, we assessed the gene expression in the left ventricle of diabetic and non-diabetic mice using Affymetrix microarray analysis. Allograft inflammatory factor-1 (AIF-1), one of the top downregulated B cell inflammatory genes, is associated with B cell functions in inflammatory responses. Real-time reverse transcriptase-polymerase chain reaction confirmed the Affymetrix data. The expression of CD19 and AIF-1 were downregulated in diabetic hearts as compared to control hearts. Using in vitro migration assay, we showed for the first time that AIF-1 is responsible for B cell migration as B cells migrated to GFP-AIF-1-transfected H9C2 cells compared to empty vector-transfected cells. Interestingly, overexpression of AIF-1 in diabetic mice prevented streptozotocin-induced cardiac dysfunction, inflammation and promoted B cell homing into the heart. Our results suggest that AIF-1 downregulation inhibited B cell homing into diabetic hearts, thus promoting inflammation that leads to the development of diabetic cardiomyopathy, and that overexpression of AIF-1 could be a novel treatment for this condition.

糖尿病（Diabetes mellitus, DM）常引发心脏的慢性炎症、心肌肥大、细胞凋亡与纤维化，进而导致心肌重构、心功能减退及心力衰竭。然而，此类心脏疾病的具体病因尚未明确。为此，我们采用Affymetrix基因芯片分析技术，检测了糖尿病小鼠与非糖尿病小鼠左心室的基因表达水平。移植排斥反应炎症因子-1（Allograft inflammatory factor-1, AIF-1）是表达下调最显著的B细胞炎症基因之一，其与炎症应答过程中的B细胞功能密切相关。实时逆转录聚合酶链反应（Real-time reverse transcriptase-polymerase chain reaction）验证了Affymetrix的实验结果。与对照组心脏相比，糖尿病小鼠心脏中CD19与AIF-1的表达均出现下调。通过体外细胞迁移实验，我们首次证实AIF-1可介导B细胞迁移：相较于转染空载体的H9C2细胞，B细胞会向表达GFP-AIF-1的H9C2细胞发生定向迁移。值得注意的是，在糖尿病小鼠体内过表达AIF-1，可阻断链脲佐菌素诱导的心脏功能损伤与炎症反应，并促进B细胞向心脏组织归巢。本研究结果表明，AIF-1表达下调会抑制B细胞向糖尿病心脏归巢，进而加剧炎症反应，最终推动糖尿病心肌病的发生发展；而过表达AIF-1或可成为该疾病的全新治疗策略。