Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Dalian Medical University, Dalian 116044, China.
Int J Cardiol. 2019 Jan 15;275:120-128. doi: 10.1016/j.ijcard.2018.06.029. Epub 2018 Jun 8.
Low-density lipoprotein receptor-related protein 5 (LRP5) has been intensively studied as a co-receptor for β-catenin-dependent Wnt signaling. Emerging evidences have demonstrated β-catenin-independent functions of LRP5. However, the biological role of LRP5 in the mammalian heart is largely unknown.
Conditional cardiac-specific Lrp5 knockout (Lrp5-CKO) mice were generated by crossing Lrp5 mice with αMHC/MerCreMer mice. Lrp5-CKO mice consistently displayed normal cardiac structure and function. Telemetric electrocardiogram recordings revealed a short QT interval in Lrp5-CKO mice, which was tightly linked to the striking abbreviation of action potential duration (APD) in ventricular myocytes. The analysis of whole-cell currents indicated that a reduction in activity and protein expression of L-type calcium channel (LTCC), rather than other ion channels, contributed to the abnormality in APD. Furthermore, we showed that Lrp5 ablation induced a significant convergence of Ca1.2α1c proteins to the endoplasmic reticulum. Consequently, increased proteasomal degradation of these proteins was observed, which was independent of the Wnt/β-catenin signaling pathway.
LRP5 directly modulates the degradation of LTCC to control cardiac QT interval. These findings provide compelling evidence for the potential role of LRPs in cardiac electrophysiology.
低密度脂蛋白受体相关蛋白 5（LRP5）作为β-连环蛋白依赖性 Wnt 信号的共受体受到了广泛研究。新出现的证据表明 LRP5 具有β-连环蛋白非依赖性功能。然而，LRP5 在哺乳动物心脏中的生物学作用在很大程度上仍是未知的。
通过将 Lrp5 小鼠与αMHC/MerCreMer 小鼠杂交，生成了条件性心脏特异性 Lrp5 敲除（Lrp5-CKO）小鼠。Lrp5-CKO 小鼠始终表现出正常的心脏结构和功能。遥测心电图记录显示 Lrp5-CKO 小鼠的 QT 间期缩短，这与心室肌细胞动作电位时程（APD）的显著缩短密切相关。全细胞膜电流分析表明，L 型钙通道（LTCC）的活性和蛋白表达减少，而不是其他离子通道，导致了 APD 的异常。此外，我们表明 Lrp5 缺失诱导 Ca1.2α1c 蛋白大量聚集到内质网。因此，这些蛋白的蛋白酶体降解增加，这与 Wnt/β-连环蛋白信号通路无关。
LRP5 直接调节 LTCC 的降解以控制心脏 QT 间期。这些发现为 LRPs 在心脏电生理学中的潜在作用提供了有力的证据。
