Inhibition of Sema4D attenuates pressure overload-induced pathological myocardial hypertrophy via the MAPK/NF-κB/NLRP3 pathways

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 hypertr...

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Veröffentlicht in:Biochimica et biophysica acta. Molecular basis of disease 2024-03, Vol.1870 (3), p.166944-166944, Article 166944
Hauptverfasser: Wu, Bing, Xu, Cheng, Xu, Changwu, Qiu, Liqiang, Gao, Ji-Xian, Li, Ming, Xiong, Yuanguo, Xia, Hao, Xia, Zhongyuan, Liu, Xiaoxiong
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Sprache:eng
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Zusammenfassung: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 MAPK 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. In this study, we identify Sema4D as a positive regulator and a new therapeutic target of pathological cardiac hypertrophy and heart failure. The major findings and the novelty of this study are listed below:•Increased expression of Sema4D was observed in both murine hypertrophic hearts and angiotensin II-treated cardiomyocytes.•Upregulation of Sema4D in mice aggravated the pressure overload-induced cardiac hypertrophy, which can be alleviated by Sema4D knockdown.•Sema4D promoted the activation of MAPK/NF-κB/NLRP3 pathway in response to hypertrophic stress.•MEK inhibition rescued the deleterious effects in Sema4D overexpression mice induced by TAC.
ISSN:0925-4439
1879-260X
DOI:10.1016/j.bbadis.2023.166944