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Published on: July 10, 2019
Deficiency in nucleoside diphosphate kinase B leads to endothelial activation of the hexosamine biosynthesis pathway
Feng Shao1, Johanna Wieland1,2, Yixin Wang1
1Experimental Pharmacology Mannheim, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Str. 13-17, 68167, Mannheim, Germany.
Insights
Nucleoside diphosphate kinase B (NDPKB) deficiency causes heart problems by activating the hexosamine biosynthesis pathway (HBP) in endothelial cells. This leads to cardiac dysfunction and highlights HBP's role in cardiovascular health.
Area of Science:
- Cardiovascular Biology
- Metabolic Pathways
- Cellular Signaling
Background:
- Nucleoside diphosphate kinase B (NDPKB) deficiency in endothelial cells (ECs) is linked to hexosamine biosynthesis pathway (HBP) activation and retinal vascular damage.
- The study investigates the cardiac consequences of NDPKB deficiency in a mouse model.
Purpose of the Study:
- To determine the effects of NDPKB deficiency on cardiac function and structure.
- To elucidate the role of the hexosamine biosynthesis pathway (HBP) in NDPKB-deficient hearts.
Main Methods:
- Utilized NDPKB-deficient mice and assessed cardiac function via echocardiography.
- Analyzed cardiomyocyte contractility using hiPSC-derived cardiomyocytes (hiPSC-CMs) and IonOptix system.
- Performed immunoblotting and immunofluorescence to examine protein expression and localization in cardiac tissues and cells.
Main Results:
- NDPKB deficient mice exhibited impaired glucose tolerance, cardiac hypertrophy, and diastolic dysfunction.
- Reduced phosphorylation of phospholamban (PLN) and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) expression were observed.
- Activation of the HBP and O-GlcNAc cycle, along with fibrosis and TGF-β upregulation, occurred in NDPKB-deficient hearts and cardiac ECs.
Conclusions:
- NDPKB deficiency triggers endothelial HBP activation, leading to cardiac dysfunction.
- Proper endothelial HBP function is critical for maintaining cardiovascular homeostasis.
Background:
Nucleoside diphosphate kinase B (NDPKB) deficiency in endothelial cells (ECs) promotes the activation of the hexosamine biosynthesis pathway (HBP), leading to vascular damage in the retina. The aim of this study was to investigate the consequences of NDPKB deficiency in the mouse heart.
Methods:
NDPKB deficient mice were used in the study. Echocardiography was employed to assess cardiac function in vivo. Characterization of contractility in hiPSC-derived cardiomyocytes (hiPSC-CMs) was measured with the IonOptix contractility system. Immunoblotting and immunofluorescence were carried out to analyze the expression and localization of proteins in cultured cells and left ventricles (LVs).
Results:
NDPKB deficient mice displayed impaired glucose tolerance and increased heart weight compared to controls. Echocardiographic analysis revealed an increase in the diastolic diameter of the left ventricular posterior wall (LVPW), a decrease in the early diastolic mitral valve E and E' wave, and in the ratios of E/A and E'/A' in NDPKB deficient hearts, suggesting cardiac hypertrophy and diastolic dysfunction. In line with cardiac dysfunction, the phosphorylation of myocardial phospholamban (PLN) and the expression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) in the NDPKB deficient LVs were significantly reduced. Moreover, the accumulation of collagen, fibronectin as well as the upregulation of transforming growth factor β (TGF-β), were detected in NDPKB deficient LVs. In addition, activation of the HBP and its downstream O-GlcNAc cycle was observed in the LVs and cardiac ECs (CECs) isolated from the NDPKB-/- mice. Furthermore, a bipolar O-GlcNAc regulation was identified in CMs. O-GlcNAc was decreased in NDPKB-depleted CMs, while conditioned medium from NDPKB-depleted ECs significantly increased O-GlcNAc levels, along with contractile and relaxation dysfunction of the hiPSC-CMs, which was attenuated by inhibiting endothelial HBP activation.
Conclusions:
Deficiency in NDPKB leads to endothelial activation of the HBP and cardiac dysfunction. Our findings may highlight the crucial role of proper endothelial HBP in maintaining cardiovascular homeostasis.
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