Deficiency in nucleoside diphosphate kinase B leads to endothelial activation of the hexosamine biosynthesis pathway and cardiac dysfunction

• DOI: 10.1186/s12933-025-02633-8
• Publication Date: 2025-02-21T16:35:00Z
• Authors: Feng Shao; Johanna Wieland; Yixin Wang; Merve Keles; Zenghui Meng; Santosh Lomada; Miao Qin; Veronika Leiss; Abel Martin-Garrido; Manuela Fuhrmann; Yi Qiu; Felix A. Trogisch; Christiane Vettel; Joerg Heineke; Yuxi Feng
• Keywords: Phospholamban; Contractility

Abstract Background Nucleoside diphosphate kinase B (NDPKB) deficiency in endothelial cells (ECs) promotes the activation of hexosamine biosynthesis pathway (HBP), leading to vascular damage retina. The aim this study was investigate consequences NDPKB mouse heart. Methods deficient mice were used study. Echocardiography employed assess cardiac function vivo. Characterization contractility hiPSC-derived cardiomyocytes (hiPSC-CMs) measured with IonOptix system. Immunoblotting and immunofluorescence carried out analyze expression localization proteins cultured left ventricles (LVs). Results displayed impaired glucose tolerance increased heart weight compared controls. Echocardiographic analysis revealed an increase diastolic diameter ventricular posterior wall (LVPW), a decrease early mitral valve E E′ wave, ratios E/A E′/A′ hearts, suggesting hypertrophy dysfunction. In line dysfunction, phosphorylation myocardial phospholamban (PLN) sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase 2 (SERCA2) LVs significantly reduced. Moreover, accumulation collagen, fibronectin as well upregulation transforming growth factor β (TGF-β), detected LVs. addition, HBP its downstream O-GlcNAc cycle observed ECs (CECs) isolated from −/− mice. Furthermore, bipolar regulation identified CMs. decreased NDPKB-depleted CMs, while conditioned medium levels, along contractile relaxation dysfunction hiPSC-CMs, which attenuated by inhibiting activation. Conclusions Deficiency leads Our findings may highlight crucial role proper maintaining cardiovascular homeostasis.