Laboratorio di Patologia Cellulare e Molecolare, San Raffaele Pisana, Istituto di Ricovero e Cura a Carattere Scientifico, Rome-IRCCS, Italy.
Mol Ther. 2013 Oct;21(10):1841-51. doi: 10.1038/mt.2013.137. Epub 2013 Jun 13.
Exogenous high-mobility group box 1 protein (HMGB1) administration to the mouse heart, during acute myocardial infarction (MI), results in cardiac regeneration via resident c-kit(+) cell (CPC) activation. Aim of the present study was to identify the molecular pathways involved in HMGB1-induced heart repair. Gene expression profiling was performed to identify differentially expressed genes in the infarcted and bordering regions of untreated and HMGB1-treated mouse hearts, 3 days after MI. Functional categorization of the transcripts, accomplished using Ingenuity Pathway Analysis software (IPA), revealed that genes involved in tissue regeneration, that is, cardiogenesis, vasculogenesis and angiogenesis, were present both in the infarcted area and in the peri-infarct zone; HMGB1 treatment further increased the expression of these genes. IPA revealed the involvement of Notch signaling pathways in HMGB1-treated hearts. Importantly, HMGB1 determined a 35 and 58% increase in cardiomyocytes and CPCs expressing Notch intracellular cytoplasmic domain, respectively. Further, Notch inhibition by systemic treatment with the γ-secretase inhibitor DAPT, which blocked the proteolytic activation of Notch receptors, reduced the number of CPCs, their proliferative fraction, and cardiomyogenic differentiation in HMGB1-treated infarcted hearts. The present study gives insight into the molecular processes involved in HMGB1-mediated cardiac regeneration and indicates Notch signaling as a key player.
外源性高迁移率族蛋白 B1（HMGB1）在急性心肌梗死（MI）期间给药于小鼠心脏，通过驻留的 c-kit(+)细胞（CPC）激活导致心脏再生。本研究的目的是确定 HMGB1 诱导心脏修复所涉及的分子途径。进行基因表达谱分析以鉴定未经处理和 HMGB1 处理的小鼠心脏梗死和边界区域中差异表达的基因，在 MI 后 3 天。使用 IPA（Ingenuity Pathway Analysis）软件对转录物进行功能分类，结果表明，参与组织再生的基因，即心肌发生、血管发生和血管生成，存在于梗死区和梗死周围区；HMGB1 处理进一步增加了这些基因的表达。IPA 揭示了 Notch 信号通路在 HMGB1 处理的心脏中的参与。重要的是，HMGB1 分别使 Notch 细胞内细胞质结构域表达的心肌细胞和 CPC 增加了 35%和 58%。此外，通过系统给予 γ-分泌酶抑制剂 DAPT（其阻断 Notch 受体的蛋白水解激活）抑制 Notch，减少了 CPC 的数量、其增殖分数以及在 HMGB1 处理的梗死心脏中的心肌生成分化。本研究深入了解了 HMGB1 介导的心脏再生所涉及的分子过程，并表明 Notch 信号作为关键参与者。
