BACKGROUND Latrophilin-2 (Lphn2), an adhesive GPCR (G protein-coupled receptor), was found to be a specific marker of cardiac progenitors during the differentiation of pluripotent stem cells into cardiomyocytes or during embryonic heart development in our previous studies. Its role in adult heart physiology, however, remains unclear. METHODS The embryonic lethality resulting from Lphn2 deletion necessitates the establishment of cardiomyocyte-specific, tamoxifen-inducible Lphn2 knockout mice, which was achieved by crossing Lphn2 flox/flox mice with mice having MerCreMer (tamoxifen-inducible Cre [Cyclization recombinase] recombinase) under the α-myosin heavy chain promoter. RESULTS Tamoxifen treatment for several days completely suppressed Lphn2 expression, specifically in the myocardium, and induced the dilated cardiomyopathy (D-CMP) phenotype with serious arrhythmia and sudden death in a short period of time. Transmission electron microscopy showed mitochondrial abnormalities, blurred Z-discs, and dehiscent myofibrils. The D-CMP phenotype, or heart failure, worsened during myocardial infarction. In a mechanistic study of D-CMP, Lphn2 knockout suppressed PGC-1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) and mitochondrial dysfunction, leading to the accumulation of reactive oxygen species and the global suppression of junctional molecules, such as N-cadherin (adherens junction), DSC-2 (desmocollin-2; desmosome), and connexin-43 (gap junction), leading to the dehiscence of cardiac myofibers and serious arrhythmia. In an experimental therapeutic trial, activators of p38-MAPK (p38 mitogen-activated protein kinases), which is a downstream signaling molecule of Lphn2, remarkably rescued the D-CMP phenotype of Lphn2 knockout in the heart by restoring PGC-1α and mitochondrial function and recovering global junctional proteins. CONCLUSIONS Lphn2 is a critical regulator of heart integrity by controlling mitochondrial functions and cell-to-cell junctions in cardiomyocytes. Its deficiency leads to D-CMP, which can be rescued by activators of the p38-MAPK pathway.

中文翻译：

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心肌细胞中的 Latrophilin-2 缺失会破坏细胞连接，导致 D-CMP。


背景 Latrophilin-2 （Lphn2） 是一种粘附性 GPCR （G 蛋白偶联受体），在我们之前的研究中被发现是多能干细胞分化为心肌细胞或胚胎心脏发育过程中心脏祖细胞的特异性标志物。然而，它在成人心脏生理学中的作用仍不清楚。方法 Lphn2 缺失导致的胚胎致死性需要建立心肌细胞特异性、他莫昔芬诱导的 Lphn2 敲除小鼠，这是通过将 Lphn2 flox/flox 小鼠与在 α-肌球蛋白重链启动子下具有 MerCreMer （他莫昔芬诱导的 Cre [环化重组酶] 重组酶） 的小鼠杂交来实现的。结果 他莫昔芬治疗数天完全抑制了 Lphn2 的表达，特别是在心肌中，并在短时间内诱导了严重心律失常和猝死的扩张型心肌病 （D-CMP） 表型。透射电子显微镜检查显示线粒体异常、Z 盘模糊和肌原纤维开裂。D-CMP 表型或心力衰竭在心肌梗死期间恶化。在 D-CMP 的机制研究中，Lphn2 敲除抑制了 PGC-1α （过氧化物酶体增殖物激活受体 γ 共激活因子 1-α） 和线粒体功能障碍，导致活性氧的积累和连接分子的整体抑制，如 N-钙粘蛋白 （粘附连接）、DSC-2 （结氨蛋白-2;桥粒） 和连接蛋白-43 （间隙连接），导致心肌纤维裂开和严重的心律失常。 在一项实验性治疗试验中，p38-MAPK（p38 丝裂原活化蛋白激酶）的激活剂是 Lphn2 的下游信号分子，通过恢复 PGC-1α 和线粒体功能并恢复整体连接蛋白，显着挽救了心脏中 Lphn2 敲除的 D-CMP 表型。结论 Lphn2 通过控制心肌细胞中的线粒体功能和细胞间连接，是心脏完整性的关键调节因子。它的缺陷导致 D-CMP，它可以被 p38-MAPK 通路的激活剂挽救。