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Fumarate hydratase ameliorates pressure overload induced cardiac remodeling by controlling Elovl7-mediated biosynthesis of unsaturated fatty acids

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Pathological cardiac hypertrophy as a major contributor to heart failure is characterized by complicated mechanisms. Fumarate hydratase (FH) is a crucial enzyme in the tricarboxylic acid cycle. FH mutations and dysfunction have been implicated in various pathological processes including hereditary leiomyomatosis and renal cell cancer, neurodegenerative diseases, metabolic syndrome and cardiovascular diseases. In this study we investigated the role of FH in cardiac hypertrophy. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC) surgery as well as in neonatal rat cardiomyocytes (NRCMs) by phenylephrine (PE) stimulation. We showed that the expression levels of FH were gradually increased with development of cardiac hypertrophy in TAC mice. Cardiomyocyte-specific overexpression of FH by intravenous injection of recombinant adeno-associated virus serotype 9 (AAV9) carrying FH two weeks before TAC surgery prevented the morphological changes, cardiac dysfunction and remodeling in TAC mice; FH overexpression also significantly attenuated PE-induced hypertrophy in NRCMs along with suppressed expression of hypertrophic markers ANP, BNP and β-MHC. We demonstrated that FH overexpression alleviated TAC-induced mitochondrial structural damage in cardiomyocytes and facilitated metabolic remodeling. RNA sequencing and untargeted metabolomics revealed that FH overexpression mitigated myocardial remodeling and mitochondrial metabolism dysfunction in TAC mice mainly by suppressing the transcription factor SREBP and reducing the gene expression of elongation of very long chain fatty acids protein 7 (Elovl7). Overexpression of Elovl7 reversed the protective effects of FH in both TAC mice and PE-stimulated NRCMs. Knockdown of the transcription factor SREBP reduced Elovl7 expression, thereby exerting cardioprotective effects. In conclusion, we demonstrate that FH overexpression prevents cardiac hypertrophy in mice by regulating glucose and lipid metabolism through the malate-SREBP-Elovl7 pathway.

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Fig. 1: Upregulation of FH in cardiomyocytes is associated with chronic pressure overload-induced cardiomyocyte hypertrophy.
Fig. 2: FH overexpression reverses cardiac dysfunction and hypertrophy induced by 4 weeks of TAC.
Fig. 3: FH overexpression reverses pathological cardiac remodeling.
Fig. 4: FH overexpression inhibits TAC-induced mitochondrial fusion and division, preserving normal mitochondrial morphology and function.
Fig. 5: Metabolome analysis indicates that FH enhances myocardial energy production by decreasing glycolytic activity and limiting lipid accumulation.
Fig. 6: Overexpression of FH regulates glucose and lipid metabolism by reducing Elovl7 expression.
Fig. 7: Overexpression of FH regulates glucose and lipid metabolism by increasing malic acid levels, which inhibits the activity of SREBP and thereby reduces Elovl7 expression.
Fig. 8: Knockdown of Elovl7 can reverse chronic stress-induced myocardial remodeling and improve cardiac function in vivo and in vitro.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Home for Researchers editorial team (www.home-for-researchers.com) for language editing service. We thank Baiqu for providing transcriptome sequencing and non-targeted metabolome sequencing.

Funding

The authors receive support from the National Key R&D Program of China (2018YFC1311300); the National Natural Science Foundation of China (Nos: 82170245, 81860080, and 82070204); and the Regional Innovation and Development Joint Fund of National Natural Science Foundation of China (No. U22A20269). China Postdoctoral Science Foundation funded project (2025M772320) and Postdoctoral Innovative Talents Support Program (BX20250257), the Open Project—Seed Fund Project of Hubei Provincial Key Laboratory (2024KFZ021).

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  1. These authors contributed equally: Lan-lan Li, Chao-jun Sun

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  1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Lan-lan Li, Chao-jun Sun, Xiao-tong Mo, Yun Xing, Tong Zhang, Heng Zhang, Nan Zhao, Yan-yan Meng, Sai-yang Xie & Wei Deng

  2. Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China

    Lan-lan Li, Chao-jun Sun, Xiao-tong Mo, Yun Xing, Tong Zhang, Heng Zhang, Nan Zhao, Yan-yan Meng, Sai-yang Xie & Wei Deng

  3. Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China

    Xiao-feng Zeng & Sha-sha Wang

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Contributions

LLL and CJS: designed research; performed research; contributed new reagents; analyzed data and wrote the paper; SYX: Contributed new reagents and analyzed data; XTM, YX, and TZ: Responsible for most of the experiments; WD and YYM: Funding support and final paper guidance and review; Others: Participated in some experiment.

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Correspondence to Yan-yan Meng, Sai-yang Xie or Wei Deng.

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Li, Ll., Sun, Cj., Mo, Xt. et al. Fumarate hydratase ameliorates pressure overload induced cardiac remodeling by controlling Elovl7-mediated biosynthesis of unsaturated fatty acids. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01637-0

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