Sema4D (CD100)与病理和生理过程密切相关，包括肿瘤生长、血管生成和心脏发育。然而，Sema4D在心脏肥大中的作用和机制迄今为止仍不清楚。为了评估Sema4D对病理性心脏肥大的影响，对通过尾静脉注射转染AAV9-mSema4D-shRNA或AAV9-mSema4D腺相关病毒的C57BL/6小鼠进行TAC手术。我们的结果表明，Sema4D 敲低可减轻压力超负荷时的心脏肥大、纤维化和功能障碍，并且 Sema4D 下调可显着抑制血管紧张素 II 诱导的心肌细胞肥大。同时，Sema4D过表达在体外和体内产生相反的效果。此外，信号通路分析表明，Sema4D在压力超负荷引起的心脏肥大期间激活丝裂原激活蛋白激酶激酶1/2-细胞外信号调节激酶1/2通路，以及药理丝裂原激活蛋白激酶激酶1/2抑制剂 U0126 几乎完全逆转了 Sema4D 过度表达引起的恶化表型，从而改善了心脏功能。进一步研究表明，Sema4D诱导的心肌肥厚与焦亡相关蛋白PP65、NLRP3、caspase-1、ASC、GSDMD、IL-18和IL-1β的表达密切相关。总之，我们的研究表明，Sema4D通过调节MAPK/NF-κB/NLRP3通路来调节病理性心肌肥厚的过程，Sema4D可能是心脏肥大和心力衰竭的有前途的介入靶点。版权所有©2023。由Elsevier B.V.出版。

Sema4D (CD100) is closely related to pathological and physiological processes, including tumor growth, angiogenesis and cardiac development. Nevertheless, the role and mechanism of Sema4D in cardiac hypertrophy are still unclear to date. To assess the impact of Sema4D on pathological cardiac hypertrophy, TAC surgery was performed on C57BL/6 mice which were transfected with AAV9-mSema4D-shRNA or AAV9-mSema4D adeno-associated virus by tail vein injection. Our results indicated that Sema4D knockdown mitigated cardiac hypertrophy, fibrosis and dysfunction when exposed to pressure overload, and Sema4D downregulation markedly inhibited cardiomyocyte hypertrophy induced by angiotensin II. Meanwhile, Sema4D overexpression had the opposite effect in vitro and in vivo. Furthermore, analysis of signaling pathways showed that Sema4D activated the mitogen-activated protein kinase kinase 1/2-extracellular signal-regulated kinase 1/2 pathway during cardiac hypertrophy induced by pressure overload, and the pharmacological mitogen-activated protein kinase kinase 1/2 inhibitor U0126 almost completely reversed Sema4D overexpression-induced deteriorated phenotype, resulting in improved cardiac function. Further research indicated that myocardial hypertrophy induced by Sema4D was closely related to the expression of the pyroptosis-related proteins PP65, NLRP3, caspase-1, ASC, GSDMD, IL-18 and IL-1β. In conclusion, our study demonstrated that Sema4D regulated the process of pathological myocardial hypertrophy through modulating MAPK/NF-κB/NLRP3 pathway, and Sema4D may be the promising interventional target of cardiac hypertrophy and heart failure.Copyright © 2023. Published by Elsevier B.V.