Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University.
Department of Cardiovascular Medicine, Saga University.
Circ J. 2019 Jan 25;83(2):368-378. doi: 10.1253/circj.CJ-18-0925. Epub 2018 Nov 27.
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.
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 Ca-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.
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.
心力衰竭（HF）患者数量的迅速增加与老年人数量的增加在全球范围内受到关注。HF 不仅增加死亡率，还降低生活质量，造成医疗和社会问题。因此，有必要定义 HF 发展和进展的分子机制。HMGB2 是高迁移率族蛋白超家族的成员，其特征为与 DNA 结合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 HMGB2 的缺失会导致肥大并增加与 HF 相关的基因表达。然而，其在心脏中的体内功能尚未得到评估。
Western blot 分析显示，在小鼠的横主动脉缩窄（TAC）引起的压力超负荷心脏组织中，HMGB2 的表达增加。Hmgb2 纯合敲除（Hmgb2）小鼠由于 AKT 失活和肌浆网（内质网）Ca-ATP 酶（SERCA）2a 活性降低而出现心脏功能障碍。与野生型小鼠相比，Hmgb2 小鼠在 TAC 手术后心脏功能障碍恶化，易患 HF 发展和进展。
本研究表明，心脏 HMGB2 的上调是心脏应激的适应性反应，而这种反应的丧失可能会加速心脏功能障碍，表明 HMGB2 发挥心脏保护作用。
