Department of Biochemistry, CARIM, Maastricht University, Maastricht, The Netherlands.
Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
Cell Commun Signal. 2024 Mar 27;22(1):197. doi: 10.1186/s12964-024-01546-5.
Severe cardiac remodeling leading to heart failure in individuals harboring pathogenic LMNA variants, known as cardiolaminopathy, poses a significant clinical challenge. Currently, there is no effective treatment for lamin-related diseases. Exploring the intricate molecular landscape underlying this condition, with a specific focus on abnormal mechanotransduction, will propel our understanding of cardiolaminopathy. The LMNA gene undergoes alternative splicing to create A-type lamins, a part of the intermediate filament protein family. A-type lamins are located underneath the nuclear envelope, and given their direct interaction with chromatin, they serve as mechanosensory of the cell by interacting with the cytoskeleton and safeguarding the transcriptional program of cells. Nucleated cells in the cardiovascular system depend on precise mechanical cues for proper function and adaptation to stress. Mechanosensitive signaling pathways are essential in regulating mechanotransduction. They play a pivotal role in various molecular and cellular processes and commence numerous downstream effects, leading to transcriptional activation of target genes involved in proliferation, migration, and (anti-)apoptosis. Most pathways are known to be regulated by kinases, and this area remains largely understudied in cardiomyopathies.Heart failure is linked to disrupted mechanotransduction, where LMNA mutations affect nuclear integrity, impacting the response to extracellular matrix signals and the environment. The Hippo pathway, anchored by YAP1/WWTR1, emerges as a central player by orchestrating cellular responses to mechanical signals. However, the involvement of Hippo and YAP1/WWTR1 in cardiolaminopathy is unclear and likely mutation- and tissue-specific, warranting further investigation. Here, we highlight the involvement of multiple signaling pathways in mechanotransduction in cardiolaminopathy. We delve into (non-)canonical functions of key signaling components, which may hold critical clues for understanding disease pathogenesis. In summary, we comprehensively examine the mechanobiology of A-type lamins, the role of mechanosensitive signaling pathways, and their intricate interplay in the pathogenesis of cardiolaminopathy. A better understanding of these mechanisms is paramount for developing targeted therapies and interventions for individuals afflicted with this debilitating cardiac condition. Prior studies overlooked accurate gene nomenclature in protein and pathway names. Our review addresses this gap, ensuring precision by aligning names with correct gene nomenclature.
携带致病性 LMNA 变异体的个体，即所谓的心肌 laminopathy，会导致严重的心脏重构，进而引发心力衰竭，这给临床带来了巨大的挑战。目前，针对 lamin 相关疾病尚无有效的治疗方法。深入研究该疾病的分子机制，特别是异常的机械转导机制，将有助于我们加深对心肌 laminopathy 的认识。
LMNA 基因通过可变剪接产生 A 型 lamin，后者是中间丝蛋白家族的一部分。A 型 lamin 位于核膜下方，由于其与染色质直接相互作用，因此通过与细胞骨架相互作用，充当细胞的机械感受器，并保护细胞的转录程序。心血管系统中的有核细胞依赖于精确的机械线索来实现正常功能和适应应激。机械敏感信号通路在调节机械转导中起着至关重要的作用。它们在各种分子和细胞过程中发挥着核心作用，并引发众多下游效应，导致参与增殖、迁移和（抗）凋亡的靶基因的转录激活。大多数通路都已知受激酶调节，但在心肌病中，这一领域的研究仍相对较少。
心力衰竭与机械转导的中断有关，其中 LMNA 突变会影响核完整性，从而影响对细胞外基质信号和环境的反应。Hippo 通路，由 YAP1/WWTR1 锚定，通过协调细胞对机械信号的反应，成为一个核心调控因子。然而，Hippo 和 YAP1/WWTR1 在心肌 laminopathy 中的作用尚不清楚，可能与突变和组织特异性有关，需要进一步研究。在这里，我们强调了机械转导在心肌 laminopathy 中涉及的多种信号通路。我们深入探讨了关键信号成分的（非）经典功能，这些功能可能为理解疾病发病机制提供关键线索。
总之，我们全面研究了 A 型 lamin 的机械生物学、机械敏感信号通路的作用以及它们在心肌 laminopathy 发病机制中的复杂相互作用。深入了解这些机制对于为患有这种衰弱性心脏疾病的个体开发靶向治疗和干预措施至关重要。先前的研究忽略了蛋白和通路名称中准确的基因命名法。我们的综述解决了这一差距，通过将名称与正确的基因命名法对齐，确保了准确性。
