Endothelial metabolic disorder in NDPKB deficient mice correlates with cardiac abnormalities

Feng Shao; Johanna Wieland; Merve Keles; Santosh Lomada; Yixin Wang; Felix Trogisch; Christiane Vettel; Thomas Wieland; Joerg Heineke; Yuxi Feng

doi:10.1055/s-0044-1785251

Diabetologie und Stoffwechsel, Table of Contents

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

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

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

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

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

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

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

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

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

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

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

Abstract

Full Text

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.