Oxidative stress in children late after Kawasaki disease: relationship with carotid atherosclerosis and stiffness

Background: Persistent arterial dysfunction in patients with a history of Kawasaki disease (KD) and an integral role of oxidative stress in the development of cardiovascular disease are increasingly recognized. We sought to test the hypothesis that oxidative stress is increased in KD patients and related to carotid atherosclerotic changes and stiffness. Methods: We compared the serum levels of oxidative stress biomarkers, carotid intima-media thickness (IMT), and carotid stiffness index among KD patients with coronary aneurysms (n = 32), those without coronary complications (n = 19), and controls (n = 32). Results: Compared with controls, patients with coronary aneurysms had significantly higher serum levels of malonaldehyde (2.62 ± 0.12 μM vs 2.22 ± 0.07 μM, p = 0.014) and hydroperoxides (26.50 ± 1.13 μM vs 22.50 ± 0.62 μM, p = 0.008). A linear trend of the magnitude of oxidative stress in relation to inflammatory damage was observed for malonaldehyde (p = 0.018) and hydroperoxides (p = 0.014) levels. Serum malonaldehyde and hydroperoxide levels correlated positively with carotid IMT (p < 0.001 and p = 0.034, respectively) and stiffness index (p = 0.001 and p = 0.021, respectively). Multiple linear regression analysis identified serum malonaldehyde level as a significant determinant of carotid IMT (β = 0.31, p = 0.006) and stiffness (β = 0.27, p = 0.008). Conclusion: Our findings suggestoxidative stress is increased in KD patients with coronary aneurysms and is associated with carotid intima-media thickening and stiffening. © 2008 Cheung et al; licensee BioMed Central Ltd.published_or_final_versio

Homocysteine activates cAMP-response element binding protein in HepG2 through cAMP/PKA signaling pathway

Objective - Hyperhomocysteinemia is an independent risk factor for cardiovascular disorders. Our previous studies demonstrated that hyperhomocysteinemia not only elicited inflammatory responses in the vascular endothelium but also induced fatty liver and hypercholesterolemia via transcriptional regulation. One of the transcription factors activated in the liver during hyperhomocysteinemia was cAMP-response element binding protein (CREB). CREB regulates the expression of many genes including those involved in lipid and glucose metabolism. In this study, we investigated the molecular mechanism by which Hcy activated CREB in rat liver and in hepatocytes (HepG2). Method and Results - Hyperhomocysteinemia was induced in rats by feeding high-methionine diet for 4 weeks. There was a significant increase in hepatic cAMP levels, protein kinase A (PKA) activity and an activation of CREB. Incubation of HepG2 cells with Hcy (50 to 100 μmol/L) significantly enhanced CREB phosphorylation and subsequently increased CREB/DNA binding activity. PKA was activated in Hcy-treated cells as a result of increased cellular cAMP level. Inhibition of adenylyl cyclase not only reduced the intracellular cAMP levels elevated by Hcy treatment but also inhibited PKA activation and prevented Hcy-induced CREB phosphorylation. Conclusion - These results suggest that the cAMP/PKA signaling pathway plays an important role in mediating Hcy-induced CREB activation in hepatocyte. © 2006 American Heart Association, Inc.link_to_subscribed_fulltex

Role of folate in non-alcoholic fatty liver disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver conditions that are characterized by steatosis, inflammation, fibrosis and liver injury. The global prevalence of NAFLD is rapidly increasing in proportion to the rising incidence of obesity and type 2 diabetes. Since NAFLD is a multifaceted disorder with many underlying metabolic abnormalities, currently, there is no pharmacological agent that is therapeutically approved for the treatment of this disease. Folate is a water-soluble B vitamin that plays an essential role in one-carbon transfer reactions involved in nucleic acid biosynthesis, methylation reactions and sulfur-containing amino acid metabolism. The liver is the primary organ responsible for storage and metabolism of folates. Low serum folate levels have been observed in patients with obesity and diabetes. It has been reported that a low level of endogenous folates in rodents perturbs folate-dependent one-carbon metabolism, and may be associated with development of metabolic diseases such as NAFLD. This review highlights the biological role of folate in the progression of NAFLD and its associated metabolic complications including obesity and type 2 diabetes. Understanding the role of folate in metabolic disease may position this vitamin as a potential therapeutic for NAFLD.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Combined effects of endothelin-1 and platelet activating factor on rat aorta vasoconstriction

Endothelin (ET-1) is a potent vasoconstrictor derived from endothelial cells. Platelet activating actor (PAF) is a phospholipid mediator synthesized by a variety of cell types. ET-1 and PAF may play important roles in modulating vasomotor tone and blood pressure. Little is known about their combined vasoconstrictive effects. The objective of this study was to investigate the combined effects of ET-1 and PAF on the rat aorta. Thoracic aortic rings of rats were suspended in organ baths and ET-1 (5nM) and PAF (10nM) were added. Contractions of aortic rings were measured by transducers. PAF significantly potentiated and prolonged ET-1 induced vasoconstriction which was endothelium-independent. However, PAF alone did not induce constriction of aortic ring. Indomethacin (cyclooxygenase inhibitor) did not inhibit ET-1 induced vasoconstriction but significantly inhibited PAF potentiated ET-1 induced vasoconstriction. When phosphoramidon (an inhibitor of endothelin converting enzyme) was added to the organ bath, the combined effect of PAF and ET-1 on vasoconstriction was not affected. This result suggests that PAF potentiated vasoconstriction is not due to the synthesis of ET-1. In conclusion, our results demonstrate that PAF potentiated ET-1 induced vasoconstriction may take part in aortic smooth muscle cells via the cyclooxygenase pathway.link_to_subscribed_fulltex