Loss of Endogenous HMGB2 Promotes Cardiac Dysfunction and Pressure Overload-Induced Heart Failure in Mice
Loss of Endogenous HMGB2 Promotes Cardiac Dysfunction and Pressure Overload-Induced Heart Failure in Mice
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DOI：
10.1253/circj.cj-18-0925
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发表时间：
2019-02-01
影响因子：
3.3
通讯作者：
Oike, Yuichi
中科院分区：
文献类型：
--
作者：
Sato, Michio;Miyata, Keishi;Oike, Yuichi
背景资料：心力衰竭（HF）患者数量的快速增加与老年人数量的增加同时引起了全世界的关注。HF不仅增加死亡率，而且降低生活质量，造成医疗和社会问题。因此，有必要确定HF发生和进展的分子机制。HMGB 2是高迁移率族超家族的成员，其特征在于结合DNA以稳定核小体并促进转录的核蛋白。最近的一项体外研究表明，心肌细胞中HMGB 2的丢失会导致肥大并增加HF相关基因的表达。然而，它的在体内的心脏功能还没有assessed.Methods和结果：Western印迹分析显示增加HMGB 2表达在小鼠的心脏组织中经历压力超负荷的横向主动脉缩窄（TAC）。Hmgb 2纯合子敲除（Hmgb 2（-/-））小鼠表现出由于AKT失活和肌浆网Ca 2 +-ATP酶（SERCA）2a活性降低而导致的心功能障碍。与野生型小鼠相比，HMGB 2（-/-）小鼠TAC手术后心脏功能障碍恶化，易患小鼠HF的发展和progress.Conclusions：这项研究表明，心脏HMGB 2的上调是一种适应性反应，心脏应激，这种反应的损失可能会加速心功能障碍，这表明HMGB 2起心脏保护作用。
Background: The rapid increase in the number of heart failure (HF) patients in parallel with the increase in the number of older people is receiving attention worldwide. HF not only increases mortality but decreases quality of life, creating medical and social problems. Thus, it is necessary to define molecular mechanisms underlying HF development and progression. HMGB2 is a member of the high-mobility group superfamily characterized as nuclear proteins that bind DNA to stabilize nucleosomes and promote transcription. A recent in vitro study revealed that HMGB2 loss in cardiomyocytes causes hypertrophy and increases HF-associated gene expression. However, it's in vivo function in the heart has not been assessed.Methods and Results: Western blotting analysis revealed increased HMGB2 expression in heart tissues undergoing pressure overload by transverse aorta constriction (TAC) in mice. Hmgb2 homozygous knockout (Hmgb2(-/-)) mice showed cardiac dysfunction due to AKT inactivation and decreased sarco(endo) plasmic reticulum Ca2+-ATPase (SERCA)2a activity. Compared to wild-type mice, Hmgb2(-/-) mice had worsened cardiac dysfunction after TAC surgery, predisposing mice to HF development and progression.Conclusions: This study demonstrates that upregulation of cardiac HMGB2 is an adaptive response to cardiac stress, and that loss of this response could accelerate cardiac dysfunction, suggesting that HMGB2 plays a cardioprotective role.