巨噬细胞核内HMGB1在机械应力诱导心肌重构中的机制研究

High mobility group box 1 (HMGB1) is a highly conserved nuclear non-histone protein. We previously found that extracellular HMGB1, translocated from nucleus under mechanical stress, could promote myocardial remodeling, while nuclear HMGB1 could play important roles by regulating transcription factor and its downstream gene expression. Under LPS stress, macrophage nuclear HMGB1 plays the crucial roles in the survival and functions of macrophage. Macrophage, which is the most important inflammatory cell in myocardial tissue, involves in myocardial remodeling under mechanical stress. However, the roles and mechanisms of macrophage nuclear HMGB1 in myocardial remodeling remain unknown. Now, we have got HMGB1 conditional knockout mice and are constructing HMGB1 conditional over-expression mice. In this present study, the model of mechanical stress-induced myocardial remodeling will be established to elucidate the regulating mechanisms of macrophage nuclear HMGB1 on macrophage phenotype and to illuminate the role of macrophage nuclear HMGB1 on myocardial remodeling pros and cons by the two kinds of mice. Futhermore, the regulating mechanisms of macrophage nuclear HMGB1 on macrophage phenotype, which may through regulating transcription factors, will be confirmed by mechanical stretched macrophage. Ultimately, we intend to find new theory and new potential therapeutic targets for hypertension-induced myocardial remodeling.

高迁移率族蛋白B1（HMGB1）是一种高度保守的核内非组蛋白。前期我们研究发现，机械应力可诱导核内HMGB1向胞外转移进而促进心肌重构，而核内的HMGB1可通过调节转录因子及下游基因表达进而发挥重要作用。在LPS应激下，巨噬细胞核内HMGB1对巨噬细胞存活、功能起了关键作用。而机械应力应激下，巨噬细胞是心脏中最主要的炎症细胞，也参与了心肌重构，但巨噬细胞核内HMGB1在心肌重构中的作用与机制尚不清楚。目前我们已获得HMGB1条件性敲除小鼠，并正在构建HMGB1条件性过表达小鼠。本项目拟借助这两种小鼠构建机械应力诱导心肌重构模型，从正反两方面深入探讨巨噬细胞核内HMGB1对巨噬细胞表型的调控机制及其在心肌重构中的作用；并利用体外巨噬细胞动态牵张，验证巨噬细胞核内HMGB1通过调节转录因子对巨噬细胞表型的调控机制，为高血压心肌重构提供新理论与新的潜在治疗靶点。

高迁移率族蛋白B1（HMGB1）是一种高度保守广泛分布的核内非组蛋白。前期研究发现，机械应力可诱导核内HMGB1向胞外转移发挥促炎作用而促进心肌重构，而核内的HMGB1可通过调节转录因子及下游基因表达进而发挥不同的作用。在机械应力应激下，巨噬细胞是心脏中最主要的炎症细胞，在心肌重构过程中发挥着重要作用，但巨噬细胞核内HMGB1在心肌重构中的作用与机制尚不清楚。本项目借助巨噬细胞核内HMGB1敲除和过表达小鼠，通过构建机械应力诱导心肌重构模型（TAC），从正反两方面探讨巨噬细胞核内HMGB1在心肌重构中的作用以及可能机制。研究结果显示：巨噬细胞核内HMGB1 过表达在正常生理情况和TAC诱导的心肌重构过程中皆没有明显的作用；巨噬细胞核内HMGB1 特异敲除不影响正常生理状态下的小鼠心功能，但能够加剧TAC诱导的心力衰竭；巨噬细胞核内HMGB1的特异敲除能够促进巨噬细胞的表型转换，促炎型巨噬细胞比例增多，促进IL-1β和GSDMD途径激活，加剧 TAC 诱导的心力衰竭。同时利用体外巨噬细胞动态牵张，验证了巨噬细胞核内HMGB1对巨噬细胞表型的调控作用，最终为高血压心肌重构提供新理论与新的潜在治疗靶点。