Diabetologie und Stoffwechsel 2024; 19(S 01): S11-S12
DOI: 10.1055/s-0044-1785251
Abstracts | DDG 2024
Freie Vorträge 3
Grundlagenforschung & Klinik Typ-1-Diabetes, andere Themen

Endothelial metabolic disorder in NDPKB deficient mice correlates with cardiac abnormalities

Authors

  • Feng Shao

    1   Medical Faculty Mannheim, Heidelberg University, Experimental Pharmacology , Mannheim, Germany

  • Johanna Wieland

    1   Medical Faculty Mannheim, Heidelberg University, Experimental Pharmacology , Mannheim, Germany

  • Merve Keles

    2   Medical Faculty Mannheim, Heidelberg University, Cardiovascular Physiology, Mannheim, Germany

  • Santosh Lomada

    1   Medical Faculty Mannheim, Heidelberg University, Experimental Pharmacology , Mannheim, Germany

  • Yixin Wang

    1   Medical Faculty Mannheim, Heidelberg University, Experimental Pharmacology , Mannheim, Germany

  • Felix Trogisch

    2   Medical Faculty Mannheim, Heidelberg University, Cardiovascular Physiology, Mannheim, Germany

  • Christiane Vettel

    1   Medical Faculty Mannheim, Heidelberg University, Experimental Pharmacology , Mannheim, Germany

  • Thomas Wieland

    1   Medical Faculty Mannheim, Heidelberg University, Experimental Pharmacology , Mannheim, Germany

  • Joerg Heineke

    2   Medical Faculty Mannheim, Heidelberg University, Cardiovascular Physiology, Mannheim, Germany

  • Yuxi Feng

    1   Medical Faculty Mannheim, Heidelberg University, Experimental Pharmacology , Mannheim, Germany
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    Endothelial deficiency of Nucleoside diphosphate kinase B (NDPKB) activates the hexosamine biosynthesis pathway (HBP) and increases the protein O-GlcNAcylation levels. NDPKB-deficient mice exhibit a similar pathology to diabetic retinopathy. In this study, we evaluated the consequence of NDPKB deficiency in the heart by assessing cardiac endothelial O-GlcNAc, as well as cardiac structure and function.

    We analyzed the expression and location of proteins by immunoblotting and immunofluorescence. Additionally, transthoracic echocardiography incorporated with pulse wave-/tissue Doppler was utilized to evaluate cardiac function.

    NDPKB-deficient mice showed a significant increase in heart weight/tibia length ratio compared to wild-type (WT) mice. The diastolic diameter of the left ventricle (LV) posterior wall measured by echocardiography revealed a significant enlargement in the NDPKB-deficient mice compared to controls, whereas the parameters for systolic function did not differ between the two groups. Tissue Doppler imaging showed a significantly decreased mitral valve E/E’ wave ratio, along with a reduced ratio of E/A and E’/A’ in the NDPKB-deficient hearts. Immunoblotting experiments demonstrated significantly enhanced protein O-GlcNAcylation in the NDPKB deficient LVs. Immunofluorescence staining further proved O-GlcNAc predominantly in the cardiac vasculature. A significant increase in protein O-GlcNAcylation was detected in the endocardium of NDPKB-deficient hearts. In vitro experiments involving siRNA-mediated NDPKB knockdown in endothelial cells resulted in the accumulation of excessive fibronectin, an extracellular matrix protein, along with activation of the HBP. Furthermore, fibronectin was expressed significantly higher in NDPKB-deficient LVs compared to controls as shown in immunoblotting and Immunofluorescence staining.

    Our study demonstrated that cardiac endothelial metabolic disorder in NDPKB-deficient mice may contribute to the development of cardiac hypertrophy along with extracellular matrix accumulation and diastolic dysfunction.


     

    Interessenkonflikt

    Feng Shao and Johanna Wieland contributed equally to this work. All authors declare that they have no conflicts of interest.

    Publikationsverlauf

    Artikel online veröffentlicht:
    18. April 2024

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