The NDPKB deficient mouse as a proper novel model for the study of cardiomyopathy associated with metabolic disorder

Feng Shao (Mannheim)1, J. Wieland (Mannheim)1, M. Keles (Mannheim)2, S. Lomada (Mannheim)1, Y. Wang (Mannheim)1, F. A. Trogisch (Mannheim)2, C. Vettel (Mannheim)1, T. Wieland (Mannheim)1, J. Heineke (Mannheim)2, Y. Feng (Mannheim)1

1Medizinische Fakultät Mannheim der Universität Heidelberg Experimental Pharmacology Mannheim, Deutschland; 2Medical Faculty Mannheim of the University of Heidelberg Cardiovascular Physiology Mannheim, Deutschland


Aim: Nucleosides diphosphate kinase B (NDPKB) deficiency in endothelial cells promotes the activation of the hexosamine biosynthesis pathway (HBP), and causes vascular damage in the retina, leading to a pathology similar to diabetic retinopathy. The aim of this study was to investigate whether a diabetic cardiomyopathy-like phenotype and vascular damage occur in the hearts of NDPKB deficient mice.

Methods: 14-months old NDPKB deficient mice were used in the study. To assess left ventricle (LV) structure, systolic and diastolic function, transthoracic echocardiography, pulse wave- and tissue Doppler were employed, respectively. In addition, general parameters such as blood glucose, glycated hemoglobin, ratios of heart weight/body weight and heart weight/tibia length were analyzed . Vessels were visualized by Lectin staining. To investigate the levels and localization of O-GlcNAcylated proteins, immunofluorescence and immunoblotting were used.

Results: Blood glucose, HbA1c, and body weight did not show any significant changes between NDPKB deficient and wild type mice. However, an increase in heart weight standardized to either body weight or tibia length was observed. Echocardiography analysis in M-mode demonstrated comparable heart LV mass and diameter in NDPKB deficient and wild type mice. Nevertheless, the diastolic diameter of LV posterior wall (LVPW) was significantly thicker in the NDPKB deficient mice. There was no difference in parameters describing systolic function such as ejection fraction, fractional shortening, and cardiac output between the two groups. In contrast, tissue Doppler echocardiography demonstrated a significant decrease in mitral valve E and E' wave, E/A and E'/A' ratio, suggesting a diastolic dysfunction in the NDPKB deficient hearts. Moreover, these hearts exhibited significantly elevated protein O-GlcNAcylation in the left ventricle, indicating the activation of the HBP. O-GlcNAcylated proteins were detected predominantly in the vasculature.

Conclusions: Our study revealed that NDPKB deficiency leads to the activation of the HBP in the left ventricular vasculature. We hypothesize that the HBP activation contributes to cardiac hypertrophy and diastolic dysfunction, observed in the NDPKB deficient mouse hearts. Therefore, NDPKB deficient mice may serve as a novel model for the study of cardiomyopathy associated with altered glucose metabolism
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