Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.
Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, People's Republic of China.
J Mol Med (Berl). 2020 May;98(5):691-705. doi: 10.1007/s00109-020-01896-w. Epub 2020 Apr 12.
Cardiac hypertrophy is a complex pathological process, and the molecular mechanisms underlying hypertrophic remodeling have not been clearly elucidated. Leukocyte immunoglobulin-like receptor B4 (lilrb4) is an inhibitory transmembrane protein that is necessary for the regulation of various cellular signaling pathways. To investigate whether lilrb4 plays a role in cardiac hypertrophy, we performed aortic banding in lilrb4 knockout mice, lilrb4 cardiac-specific transgenic mice, and their wild-type littermates. Cardiac hypertrophy was evaluated by echocardiographic, hemodynamic, pathological, and molecular analyses. We found that lilrb4 was expressed both in myocardial tissue and on cultured cardiomyocytes under basal conditions, but the expression was obviously decreased in mouse hearts following aortic banding and in cardiomyocytes treated with angiotensin II. Lilrb4 disruption aggravated cardiac hypertrophy, fibrosis, and dysfunction in response to pressure overload. Conversely, the cardiac overexpression of lilrb4 led to the opposite effects. Moreover, lilrb4 overexpression inhibited angiotensin II-induced cardiomyocyte hypertrophy in vitro. Mechanistically, we determined that the cardioprotective effect of lilrb4 was mediated through an interaction with SHP-2, the preservation of phosphorylated SHP-2, and the inhibition of the NF-κB pathway. In addition, SHP-2 knockdown in cardiomyocytes eliminated the inhibitory effects of lilrb4 on angiotensin II-induced hypertrophy and NF-κB activation. Our results suggest that lilrb4 protects against pathological cardiac hypertrophy via the SHP-2-dependent inhibition of the NF-κB pathway and may act as a potential therapeutic target for cardiac hypertrophy. KEY MESSAGES: Lilrb4 expression is decreased by hypertrophic stimuli. Lilrb4 protects against pathological cardiac hypertrophy. Lilrb4 interacts with SHP-2 and inhibits NF-κB pathway.
心肌肥厚是一种复杂的病理过程，其肥厚重构的分子机制尚不清楚。白细胞免疫球蛋白样受体 B4（lilrb4）是一种抑制性跨膜蛋白，对于调节各种细胞信号通路是必需的。为了研究 lilrb4 是否在心肌肥厚中发挥作用，我们对 lilrb4 敲除小鼠、lilrb4 心脏特异性转基因小鼠及其野生型同窝仔鼠进行了主动脉缩窄术。通过超声心动图、血流动力学、病理学和分子分析评估心肌肥厚。我们发现，在基础条件下，lilrb4 在心肌组织和培养的心肌细胞中均有表达，但在主动脉缩窄后小鼠心脏和血管紧张素 II 处理的心肌细胞中表达明显降低。lilrb4 缺失加剧了心脏对压力超负荷的肥厚、纤维化和功能障碍。相反，lilrb4 在心脏中的过表达导致了相反的效果。此外，lilrb4 过表达抑制了体外血管紧张素 II 诱导的心肌细胞肥大。机制上，我们确定 lilrb4 的心脏保护作用是通过与 SHP-2 的相互作用、磷酸化 SHP-2 的保留以及 NF-κB 途径的抑制来介导的。此外，心肌细胞中 SHP-2 的敲低消除了 lilrb4 对血管紧张素 II 诱导的肥大和 NF-κB 激活的抑制作用。我们的结果表明，lilrb4 通过 SHP-2 依赖性抑制 NF-κB 途径来保护病理性心肌肥厚，并且可能成为心肌肥厚的潜在治疗靶点。
肥大刺激物可降低 lilrb4 的表达。
lilrb4 可防止病理性心肌肥厚。
lilrb4 与 SHP-2 相互作用并抑制 NF-κB 途径。
