NMR-Based Metabolomic Analysis on the Protective Effects of Apolipoprotein A-I Mimetic Peptide against Contrast Media-Induced Endothelial Dysfunction

Ting Jiang,Wei Li,Yansong Guo,Donghai Lin,Qian Du,Donghui Liu,Ping Guo,Wenqi Xu,Caihua Huang,Xianwei Xie

doi:10.3390/molecules26175123

Abstract

Endothelial dysfunction plays key roles in the pathological process of contrast media (CM)-induced acute kidney injury (CI-AKI) in patients undergoing vascular angiography or intervention treatment. Previously, we have demonstrated that an apolipoprotein A-I (apoA-I) mimetic peptide, D-4F, inhibits oxidative stress and improves endothelial dysfunction caused by CM through the AMPK/PKC pathway. However, it is unclear whether CM induce metabolic impairments in endothelial cells and whether D-4F ameliorates these metabolic impairments. In this work, we evaluated vitalities of human umbilical vein endothelial cells (HUVECs) treated with iodixanol and D-4F and performed nuclear magnetic resonance (NMR)-based metabolomic analysis to assess iodixanol-induced metabolic impairments in HUVECs, and to address the metabolic mechanisms underlying the protective effects of D-4F for ameliorating these metabolic impairments. Our results showed that iodixanol treatment distinctly impaired the vitality of HUVECs, and greatly disordered the metabolic pathways related to energy production and oxidative stress. Iodixanol activated glucose metabolism and the TCA cycle but inhibited choline metabolism and glutathione metabolism. Significantly, D-4F pretreatment could improve the iodixanol-impaired vitality of HUVECs and ameliorate the iodixanol-induced impairments in several metabolic pathways including glycolysis, TCA cycle and choline metabolism in HUVECs. Moreover, D-4F upregulated the glutathione level and hence enhanced antioxidative capacity and increased the levels of tyrosine and nicotinamide adenine dinucleotide in HUVECs. These results provided the mechanistic understanding of CM-induced endothelial impairments and the protective effects of D-4F for improving endothelial cell dysfunction. This work is beneficial to further exploring D-4F as a potential pharmacological agent for preventing CM-induced endothelial impairment and acute kidney injury.

Highlights

As the predominant diagnostic reagents, contrast media (CM) have been extensively used in clinical angiography and intravascular catheter-based intervention [1]
We revealed that iodixanol impairs cell viability, promotes vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) expression, and induces cell apoptosis in human umbilical vein endothelial cells (HUVECs) [5]
Significant Altered Metabolic Pathways Identified in HUVECs To mechanistically understand the effects of either iodixanol treatment or D-4F pretreatment on the metabolic profiles of HUVECs, we identified the significantly altered metabolic pathways by performing the metabolic pathway analyses of Iod10 vs. control group (Ctrl), Iod30 vs. Ctrl, D-4F + Iod10 vs. Iod10, and D-4F + Iod30 vs. Iod30

Summary

Introduction

As the predominant diagnostic reagents, contrast media (CM) have been extensively used in clinical angiography and intravascular catheter-based intervention [1]. Previous works have demonstrated the adverse effects of CM for patients, in particular for those high-risk patients with diabetes mellitus, heart failure and chronic kidney disease [2]. Water-soluble iodinated CM can be excreted through the kidneys, and CM-induced acute kidney injury (CI-AKI) has become the third leading cause of new-onset renal failure in hospitalized patients with CM injection [3]. CM are given via circulation during the diagnostic and interventional processes, which usually impair vascular endothelium and subsequently contribute to systemic and organ-specific adverse reactions. We revealed that iodixanol impairs cell viability, promotes vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) expression, and induces cell apoptosis in human umbilical vein endothelial cells (HUVECs) [5]. We indicated that iodixanol induces the phosphorylation of protein kinase C (PKC) beta II, p47, Rac, and endothelial nitric oxide synthase at Thr495, eliciting ROS release and ONOO− generation [5]

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Conclusion