Protective effects of sulforaphane on type 2 diabetes-induced cardiomyopathy via AMPK-mediated activation of lipid metabolic pathways and NRF2 function

  • Yike Sun
    Affiliations
    Department of Cardiology, First Hospital of Jilin University, Changchun 130021, China

    Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA
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  • Shanshan Zhou
    Affiliations
    Department of Cardiology, First Hospital of Jilin University, Changchun 130021, China
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  • Hua Guo
    Affiliations
    Department of Cardiology, First Hospital of Jilin University, Changchun 130021, China

    Department of Immunology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, China
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  • Jian Zhang
    Affiliations
    Department of Cardiology, First Hospital of Jilin University, Changchun 130021, China

    Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA
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  • Tianjiao Ma
    Affiliations
    Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA

    Department of Rheumatology and Immunology, China-Japan Union Hospital, Jilin University, Changchun 130033, China
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  • Yang Zheng
    Correspondence
    Corresponding authors at: Department of Cardiology, the First Hospital of Jilin University, No.71 Xinmin Street, Changchun 130021, China.
    Affiliations
    Department of Cardiology, First Hospital of Jilin University, Changchun 130021, China
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  • Zhiguo Zhang
    Correspondence
    Corresponding authors at: Department of Cardiology, the First Hospital of Jilin University, No.71 Xinmin Street, Changchun 130021, China.
    Affiliations
    Department of Cardiology, First Hospital of Jilin University, Changchun 130021, China
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  • Lu Cai
    Affiliations
    Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville 40202, USA

    Departments of Radiation Oncology and Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA
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Published:November 08, 2019DOI:https://doi.org/10.1016/j.metabol.2019.154002

      Highlights

      • SFN prevention of T2D-induced diabetic cardiomyopathy (DCM) is AMPKα2-dependent.
      • SFN-stimulated Nrf2-mediated antioxidative effects is AMPKα2-dependent in the heart.
      • Prevention of DCM by 3-month SFN treatment persists at least 3 more months forward.

      Abstract

      Background

      AMP-activated protein kinase (AMPK), particularly AMPKα2 isoform, plays a critical role in maintaining cardiac homeostasis. It was reported that sulforaphane (SFN) prevented type 2 diabetes (T2D)-induced cardiomyopathy accompanied by the activation of AMPK; In this study, AMPK's pivotal role in SFN-mediated prevention against T2D-induced cardiomyopathy was tested using global deletion of AMPKα2 gene (AMPKα2-KO) mice.

      Methods and results

      T2D was established by feeding 3-month high-fat diet (HFD) to induce insulin resistance, followed by an intraperitoneal injection of streptozotocin (STZ) to induce mild hyperglycemia in both AMPKα2-KO and wild-type (WT) mice. Then both T2D and control mice were subsequently treated with or without SFN for 3 months while continually feeding HFD or normal diet. Upon completion of the 3-month treatment, five mice from each group were sacrificed as a 3-month time-point (3 M). The rest continued normal diet or HFD until terminating study at the sixth month (6 M) of diabetes. Cardiac function was examined with echocardiography before sacrifice at both 3 M and 6 M. SFN prevented T2D-induced progression of cardiac dysfunction, remodeling (hypertrophy and fibrosis), inflammation, and oxidative damage in wild-type diabetic mice, but not in AMPKα2-KO mice. Mechanistically, SFN prevented T2D-induced cardiomyopathy not only by improving AMPK-mediated lipid metabolic pathways, but also enhancing NRF2 activation via AMPK/AKT/GSK3β pathway. However, these improving effects of SFN were abolished in AMPKα2-KO diabetic mice.

      Conclusions

      AMPK is indispensable for the SFN-induced prevention of cardiomyopathy in T2D, and the activation of NRF2 by SFN is mediated by AMPK/AKT/GSK3β signaling pathways.

      Keywords

      Abbreviations:

      AMPK (AMP-activated protein kinase), T2D (type 2 diabetes), SFN (sulforaphane), HFD (high-fat diet), ND (normal diet), DCM (diabetic cardiomyopathy), FAs (fatty acids), FAO (fatty acid oxidation), STZ (streptozotocin), PPAR-α (peroxisome proliferator activated receptor alpha), CPT-1B (carnitine palmitoyltransferase-1B), PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1 alpha), SCD (stearyl coenzyme A decarboxylase), GSK (glycogen synthase kinase), NRF2 (nuclear factor erythroid 2-related factor 2), COL1A1 (collagen 1A1), WGA (wheat germ agglutinin), CAT (catalase), FN (fibronectin), 4-HNE (4-hydroxynonenal), HO-1 (heme oxygenase 1), 3-NT (3-nitrotyrosine), TNF-α (tumor necrosis factor alpha), PAI-1 (plasminogen activator-inhibitor 1), ANP (atrial natriuretic peptide), AUC (area under the curves), LKB1 (liver kinase B1)
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