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Aldosterone stimulation mediates cardiac metabolism remodeling via Sirt1/AMPK signaling in canine model

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Abstract

Aldosterone (Aldo), a pivotal hormone that is ubiquitously expressed in systemic tissues of mammals, is a crucial factor in the pathogenesis of cardiac disease. Accumulating evidence suggests that disturbances in cell energy metabolism are involved in increasing aldosterone levels. However, the precise mechanism underlying the impact of cardiac metabolic remodeling underlying aldosterone stimulation remains limited. In this work, we evaluated the underlying effect of aldosterone on regulating cardiac metabolism remodeling in a canine model. Fifteen beagle dogs were divided into a control group (n = 5), Aldo group (n = 5), and a group treated with spironolactone (SP), a mineralocorticoid receptor antagonist (n = 5), for 4 weeks. Blood pressure, electrocardiogram and respiratory parameters, H&E, Masson staining, ultrastructural changes, the adenosine triphosphate (ATP) and free fatty acid (FFA) levels of ventricular tissues, the level of mRNA, and the protein expression of key metabolic factors and regulators were assessed. The Sirt1/AMPK signaling pathway was significantly inhibited in the canine model of aldosterone stimulation, resulting in a reduction of the key downstream metabolic factors involved in glucose and fatty acid oxidation. The dysregulation of expression of key factors in glycogen metabolism led to glycogen deposition, an increase in FFA levels, a reduction in ATP levels, apoptosis, inflammatory cell infiltration, and mitochondrial damage in the ventricular myocardium. These effects were significantly restored by spironolactone. Aldosterone stimulation induced cardiac metabolic remodeling in ventricular cardiomyocytes possibly through the Sirt1/AMPK signaling pathway, implying that this pathway may provide a novel therapeutic target for cardiac metabolic remodeling.

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Funding

This work was supported by grants from the National Nature Scientific Foundation of China (No. 81700305, No. 81300133, No. 81470462), the Fundamental Research Funds for the Provincial Universities (2017LCZX09), the Heilongjiang Provincial Youth Innovative Talent Training Program, and the Research Funds from the First Affiliated Hospital of Harbin Medical University (2017B006).

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Author notes

  1. Guang-zhong Liu and Song Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Youzheng Street 23#, Nangang District, Harbin, 150001, Heilongjiang Province, China

    Guang-zhong Liu, Song Zhang, Yan-yan Li, Yun Zhang, Xin-bo Zhao, Yue Yuan, Jia-wei Zhang, Zulfiia Khannanova & Yue Li

  2. Centre for Drug Safety Evaluation, Heilongjiang University of Chinese Medicine, Harbin, 150001, Heilongjiang Province, China

    Yong-wu Liu

  3. Key Laboratory of Cardiac Diseases and Heart Failure, Harbin Medical University, Harbin, 150001, Heilongjiang Province, China

    Yue Li

  4. Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, 150001, Heilongjiang Province, China

    Yue Li

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  1. Guang-zhong Liu
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Contributions

Guang Zhong Liu, Song Zhang, and Yue Li designed and conducted the experiment; Guang Zhang Liu and Song Zhang analyzed the data and wrote the manuscript. Yan Yan Li, Yong Wu Liu, Yun Zhang, Bo Xin Zhao, Yue Yuan, Jia-wei Zhang, and Zulfiia Khannanova conducted the experiments. Guang Zhong Liu, Song Zhang, and Yue Li revised the manuscript; and all authors approved the final version of the manuscript.

Corresponding author

Correspondence to Yue Li.

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Animal procedures in the present study were approved by the Animal Care and Use Committee of Harbin Medical University, and conducted in accordance with the Guide for the Care and Use of Laboratory Animals published by US National Institutes of Health (NIH Publication No. 85-23, revised 2011).

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Liu, Gz., Zhang, S., Li, Yy. et al. Aldosterone stimulation mediates cardiac metabolism remodeling via Sirt1/AMPK signaling in canine model. Naunyn-Schmiedeberg's Arch Pharmacol 392, 851–863 (2019). https://doi.org/10.1007/s00210-019-01641-2

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