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Abstract
Endothelial dysfunction is involved in the pathophysiological processes of contrast media (CM)–induced acute kidney injury (CI-AKI) after vascular angiography or intervention. Previous study found that apolipoprotein A-I (apoA-I) mimetic peptide, D-4F, alleviates endothelial impairments via upregulating heme oxygenase-1 (HO-1) expression and scavenging excessively generated reactive oxygen species (ROS). However, whether D-4F could ameliorate oxidative injuries in endothelial cells through suppressing ROS production remains unclear. In this study, a representative nonionic iodinated CM, iodixanol, was chosen for the in vitro and in vivo studies. Endothelial cell viability was assayed using micrographs, lactate dehydrogenase (LDH) activity, and cell counting kit-8 (CCK-8). Apoptosis was detected using flow cytometry analysis and caspase-3 activation. Endothelial inflammation was tested using monocyte adhesion assay and adhesion molecule expression. ROS production was detected by measuring the formation of lipid peroxidation malondialdehyde (MDA) through the thiobarbituric acid reactive substance (TBARS) assay. Peroxynitrite (ONOO⁻) formation was tested using the 3-nitrotyrosine ELISA kit. Iodixanol impaired cell viability, promoted vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) expression, and induced cell apoptosis in human umbilical vein endothelial cells (HUVECs). However, D-4F mitigated these injuries. Furthermore, iodixanol induced the phosphorylation of protein kinase C (PKC) beta II, p47, Rac1, and endothelial nitric oxide synthase (eNOS) at Thr495, which elicited ROS release and ONOO⁻ generation. D-4F inhibited NADPH oxidase (NOX) activation, ROS production, and ONOO⁻ formation via the AMP-activated protein kinase (AMPK)/PKC pathway. Additionally, after an intravascular injection of iodixanol in Sprague Dawley rats, iodixanol induced a remarkable inflammatory response in arterial endothelial cells, although significant apoptosis and morphological changes were not observed. D-4F alleviated the vessel inflammation resulting from iodixanol in vivo. Collectively, besides scavenging ROS, D-4F could also suppress ROS production and ONOO⁻ formation through the AMPK/PKC pathway, which ameliorated oxidative injuries in endothelial cells. Hence, D-4F might serve as a potential agent in preventing CI-AKI.
Highlights
Cardiovascular disease (CVD) causes disability and mortality worldwide (Joseph et al, 2017)
This study showed that D-4F inhibited reactive oxygen species (ROS) production and peroxynitrite (ONOO−) formation, improved cell viability, and ameliorated apoptosis and inflammation induced by iodixanol in human umbilical vein endothelial cells (HUVECs) via the AMPactivated protein kinase (AMPK)/protein kinase C (PKC) pathway
Iodixanol decreased the viability of HUVECs in the dose- and time-dependent manners (Figure 1A), and D-4F improved these injuries caused by iodixanol (Figure 1B)
Summary
Cardiovascular disease (CVD) causes disability and mortality worldwide (Joseph et al, 2017). Iodinated contrast media (CM) have become the most widely used reagents for diagnostic angiography and catheter-based intervention in patients with CVD (Fahling et al, 2017). CMinduced acute kidney injury (CI-AKI) is the main iatrogenic complication after intravascular CM administration, which has been the third most common reason for new-onset renal failure in hospitalized patients (Seeliger et al, 2012; Fahling et al, 2017). CM are given through circulation during the diagnostic and interventional processes. These agents impair vascular endothelium and subsequently contribute to systemic and organ-specific adverse reactions (Scoditti et al, 2013). Endothelial cell impairments caused by CM have drawn attention as the key points in the pathogenesis of CI-AKI
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