Although methylglyoxal (MGO) has emerged as key mediator of diabetic microvascular complications, the influence of MGO on the vascular transcriptome has not thoroughly been assessed. Since diabetes is associated with low grade inflammation causing sustained nuclear factor-kappa B (NF-κB) activation, the current study addressed 1) to what extent MGO changes the transcriptome of human umbilical vein endothelial cells (HUVECs) exposed to an inflammatory milieu, 2) what are the dominant pathways by which these changes occur and 3) to what extent is this affected by carnosine, a putative scavenger of MGO. Microarray analysis revealed that exposure of HUVECs to high MGO concentrations significantly changes gene expression, characterized by prominent down-regulation of cell cycle associated genes and up-regulation of heme oxygenase-1 (HO-1). KEGG-based pathway analysis identified six significantly enriched pathways of which the p53 pathway was the most affected. No significant enrichment of inflammatory pathways was found, yet, MGO did inhibit VCAM-1 expression in Western blot analysis. Carnosine significantly counteracted MGO-mediated changes in a subset of differentially expressed genes. Collectively, our results suggest that MGO initiates distinct transcriptional changes in cell cycle/apoptosis genes, which may explain MGO toxicity at high concentrations. MGO did not augment TNF-α induced inflammation.
BACKGROUND AND PURPOSE: Impairment of tissue oxygenation caused by inhomogeneous microscopic blood flow distribution, the so-called capillary transit time heterogeneity, is thought to contribute to delayed cerebral ischemia after aneurysmal SAH but has so far not been systematically evaluated in patients. We hypothesized that heterogeneity of the MTT, derived from CTP parameters, would give insight into the clinical course of patients with aneurysmal SAH and may identify patients at risk of poor outcome.
MATERIALS AND METHODS:We retrospectively analyzed the heterogeneity of the MTT using the coefficient of variation in CTP scans from 132 patients. A multivariable logistic regression model was used to model the dichotomized mRS outcome. Linear regression was used to eliminate variables with high linear dependence. T tests were used to compare the means of 2 groups. Furthermore, the time of the maximum coefficient of variation for MTT after bleeding was evaluated for correlation with the mRS after 6 months.
RESULTS:On average, each patient underwent 5.3 CTP scans during his or her stay. Patients with high coefficient of variation for MTT presented more often with higher modified Fisher (P ¼ .011) and World Federation of Neurosurgical Societies grades (P ¼ .014). A high coefficient of variation for MTT at days 3-21 after aneurysmal SAH correlated significantly with a worse mRS score after 6 months (P ¼ .016). We found no correlation between the time of the maximum coefficient of variation for MTT after bleeding and the patients' outcomes after 6 months (P ¼ .203).CONCLUSIONS: Heterogeneity of MTT in CTP after aneurysmal SAH correlates with the patients' outcomes. Because the findings are in line with the pathophysiologic concept of the capillary transit time heterogeneity, future studies should seek to verify the coefficient of variation for MTT as a potential imaging biomarker for outcome. ABBREVIATIONS: aSAH ¼ aneurysmal SAH; CTH ¼ capillary transit time heterogeneity; cvMTT ¼ coefficient of variation for MTT; cvMTT-peak ¼ maximum cvMTT after bleeding; DCI ¼ delayed cerebral ischemia; EVD ¼ external ventricular drainage; ICP ¼ intracranial pressure; RTH ¼ relative transit time heterogeneity; Tmax ¼ time-to-maximum; WFNS ¼ World Federation of Neurosurgical Societies
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