Free radical biology & medicine · 2025
Ginkgolic acid ameliorates pressure overload-induced cardiac remodeling by inhibiting SAE1 and activating the NRF2/HMOX1 pathway.
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Dang Xuening, Ji Qingqi, Huang Zhenyu, Yang Ning, Chi Chen, Zhao Yu, Xu Yiting, Wang Ming, Liu Yanyi, Jiang Zhaolei, Dai Jinjie, Li Ruogu, Gu Chang, Shi Xin, Hou Xumin, Han Wenzheng
Аннотация
BACKGROUND: Cardiac remodeling is a pathological process that progresses to heart failure (HF) characterized by high morbidity, mortality and limited therapeutic options. SUMOylation has been identified as a potential therapeutic target for this process. However, the role of SAE1(SUMO1-activating enzyme subunit 1), a marker of SUMOylation, in this process remains poorly defined. Additionally, whether Ginkgolic acid (GA), a SUMOylation inhibitor, ameliorates cardiac remodeling by inhibiting SAE1 should be further investigated.
METHODS: We analyzed the protein and mRNA expression levels of SUMOylation markers in human hypertrophy-related heart failure (HF) and mice model induced by transverse aortic constriction (TAC) samples. The direct effect of SAE1 on cardiomyocyte enlargement was examined by the SAE1 knockdown system and GA treatment. To elucidate the underlying mechanism, we integrated RNA-sequencing with interactome analysis, followed by molecular biological experimental validation, to identify the direct downstream target of SAE1. We generated cardiac-specific knockout (CKO) mice to evaluate the function of the downstream target Heme Oxygenase 1 (Hmox1) in pathological myocardial hypertrophy.
RESULTS: We first demonstrated that SAE1 increased in patients with HF and mice with TAC. GA treatment effectively suppressed SAE1 expression, attenuated cardiomyocyte hypertrophy in vitro, and ameliorated cardiac dysfunction and remodeling in TAC mice. GA administration (20mg/kg/d) significantly reduced the heart weight/body weight ratio by 22% and improved ejection fraction by approximately 25% compared to the TAC group (P < 0.0001 and P < 0.0001, respectively). Mechanistically, GA reduced the generation of reactive oxygen species (ROS) and reinstated the expression levels of the NRF2/HMOX1 pathway. Hmox1 is an essential target of SAE1 in cardiac hypertrophy. Notably, Hmox1 CKO mice largely abolished the anti-hypertrophic effects of GA.
CONCLUSION: This work identifies SAE1 as a critical driver of cardiac remodeling, and the SUMOylation inhibitor GA suppresses ROS by targeting SAE1, thereby presenting GA as a promising novel therapeutic candidate for combating heart failure.
METHODS: We analyzed the protein and mRNA expression levels of SUMOylation markers in human hypertrophy-related heart failure (HF) and mice model induced by transverse aortic constriction (TAC) samples. The direct effect of SAE1 on cardiomyocyte enlargement was examined by the SAE1 knockdown system and GA treatment. To elucidate the underlying mechanism, we integrated RNA-sequencing with interactome analysis, followed by molecular biological experimental validation, to identify the direct downstream target of SAE1. We generated cardiac-specific knockout (CKO) mice to evaluate the function of the downstream target Heme Oxygenase 1 (Hmox1) in pathological myocardial hypertrophy.
RESULTS: We first demonstrated that SAE1 increased in patients with HF and mice with TAC. GA treatment effectively suppressed SAE1 expression, attenuated cardiomyocyte hypertrophy in vitro, and ameliorated cardiac dysfunction and remodeling in TAC mice. GA administration (20mg/kg/d) significantly reduced the heart weight/body weight ratio by 22% and improved ejection fraction by approximately 25% compared to the TAC group (P < 0.0001 and P < 0.0001, respectively). Mechanistically, GA reduced the generation of reactive oxygen species (ROS) and reinstated the expression levels of the NRF2/HMOX1 pathway. Hmox1 is an essential target of SAE1 in cardiac hypertrophy. Notably, Hmox1 CKO mice largely abolished the anti-hypertrophic effects of GA.
CONCLUSION: This work identifies SAE1 as a critical driver of cardiac remodeling, and the SUMOylation inhibitor GA suppresses ROS by targeting SAE1, thereby presenting GA as a promising novel therapeutic candidate for combating heart failure.