Borrell-Pages M, Vilahur G, Romero J C, Casaní L, Bejar M T, Badimon L
Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, C/Sant Antoni Maria Claret 167, 08025, Barcelona, Spain.
Cardiovascular Research Chair, UAB-Fundación Jesús Serra, Barcelona, Spain.
Basic Res Cardiol. 2016 Nov;111(6):67. doi: 10.1007/s00395-016-0585-y. Epub 2016 Oct 4.
LRP5 (low-density lipoprotein receptor-related protein 5) activates canonical Wnt signalling. LRP5 plays multiple roles including regulation of lipoprotein and cholesterol homeostasis as well as innate immunity cell function. However, it is not known whether LRP5 has a role in the myocardium. The aim of this study was to investigate LRP5 and Wnt signalling in myocardial remodelling after acute myocardial infarction (MI). Wnt protein levels were determined in a hypercholesterolemic porcine model of MI, in Lrp5 C57Bl6 mice, in cultured cardiomyocytes and in human explanted hearts with previous MI episodes. 21 days post-MI, there was upregulation of LRP5 in the ischemic myocardium of hypercholesterolemic pigs as well as an upregulated expression of proteins of the Wnt pathway. We demonstrate via overexpression and silencing experiments that LRP5 induces Wnt pathway activation in isolated cardiomyocytes. Hypoxia and lipid-loading induced the expression of Wnt proteins, whereas this effect is blocked in LRP5-silenced cardiomyocytes. To characterize the function of the LRP5-Wnt axis upregulation in the heart, we induced MI in wild-type and Lrp5 mice. Lrp5 mice had significantly larger infarcts than Wt mice, indicating a protective role of LRP5 in injured myocardium. The LRP5 upregulation in post-MI hearts seen in pigs and mice was also evident in human hearts as dyslipidemic patients with previous episodes of ischemia have higher expression of LRP5 and Wnt-signalling genes than non-ischemic dilated hearts. We demonstrate an upregulation of LRP5 and the Wnt signalling pathway that it is a prosurvival healing response of cardiomyocytes upon injury.
低密度脂蛋白受体相关蛋白5（LRP5）可激活经典Wnt信号通路。LRP5具有多种作用，包括调节脂蛋白和胆固醇稳态以及先天免疫细胞功能。然而，LRP5在心肌中是否发挥作用尚不清楚。本研究的目的是探讨急性心肌梗死（MI）后心肌重塑过程中的LRP5和Wnt信号通路。在高胆固醇血症猪MI模型、Lrp5基因敲除的C57Bl6小鼠、培养的心肌细胞以及有过MI发作的人离体心脏中测定Wnt蛋白水平。MI后21天，高胆固醇血症猪缺血心肌中的LRP5上调，同时Wnt信号通路相关蛋白的表达也上调。我们通过过表达和沉默实验证明，LRP5可诱导分离的心肌细胞中Wnt信号通路激活。缺氧和脂质负荷可诱导Wnt蛋白表达，而在LRP5沉默的心肌细胞中这种作用被阻断。为了表征心脏中LRP5-Wnt轴上调的功能，我们在野生型和Lrp5基因敲除小鼠中诱导MI。Lrp5基因敲除小鼠的梗死面积明显大于野生型小鼠，表明LRP5对受损心肌具有保护作用。在猪和小鼠MI后心脏中观察到的LRP5上调在人心脏中也很明显，因为有过缺血发作的血脂异常患者的LRP5和Wnt信号基因表达高于非缺血性扩张型心脏。我们证明了LRP5和Wnt信号通路的上调，这是心肌细胞损伤后的一种促生存愈合反应。
