RESUMO
PURPOSE: Previous studies have independently provided evidence for the effects of HIV infection, hypothalamic-pituitary-adrenal (HPA) axis dysfunction and early life trauma on neurocognitive impairment (NCI). This study examined the interaction between single-nucleotide polymorphisms (SNPs) of two HPA axis genes, corticotrophin-releasing hormone receptor 1 (CRHR1; rs110402, rs242924, rs7209436, and rs4792888) and corticotrophin-releasing hormone-binding protein (CRHBP; rs32897, rs10062367, and rs1053989), childhood trauma, and HIV-associated NCI. PATIENTS AND METHODS: The sample comprised 128 HIV-positive Xhosa females of whom 88 (69%) had a history of childhood trauma. NCI was assessed using a battery of 17 measures sensitive to the effects of HIV, and the history of childhood trauma was assessed using the validated retrospective Childhood Trauma Questionnaire-Short Form. Generalized linear regression models were used to compare allelic distribution by trauma status and global NCI. The association between genotype, childhood trauma, and cognitive scores was also evaluated using generalized linear regression models, assuming additive models for the SNPs, and ANOVA. RESULTS: Of the seven polymorphisms assessed, only the rs10062367 variant of CRHBP was significantly associated with global NCI (P=0.034), independent of childhood trauma. This polymorphism was not significantly associated with z-scores on any specific cognitive domain. The interaction of childhood trauma and variants of CRHR1 was associated with poorer learning (rs110402) and/or recall (rs110402 and rs4792888). CONCLUSION: These findings suggest that CRHBP rs10062367 A allele is a possible risk variant for NCI in HIV, independent of childhood trauma. Furthermore, results show that the interaction of childhood trauma with variants of CRHR1, rs110402 and rs4792888, confer added vulnerability to NCI in HIV-infected individuals in cognitive domains that are known to be impacted by HIV. While these findings need independent replication in larger samples, it adds CRHBP and CRHR1 to the list of known genes linked to HIV- and childhood trauma-associated neurocognitive phenotypes.
RESUMO
UNLABELLED: The relative importance of endothelium- and cardiomyocyte-derived nitric oxide (NO) is unknown, with a lack of direct studies on cardiac microvessel endothelial cells (CMEC) and cardiomyocytes regarding relative cellular NO production. AIMS: To assess and compare baseline and hypoxia-induced NO and ONOO- production in cardiomyocytes and CMEC. METHODS: Rat cardiomyocytes were isolated, and cultured rat CMEC were purchased commercially. Hypoxia (+/- NOS inhibitors) was induced by mineral oil layering or hypoxic culture. NO and ONOO- were detected by FACS analysis of DAF-2/DA and DHR123, respectively. Total eNOS was determined by Western blot analysis. RESULTS: 1) Baseline NO production in CMEC was sevenfold (cultured cells) and 26-fold (isolated cells) higher than in cardiomyocytes, 2) eNOS expression was 22-fold higher in CMEC, 3) hypoxia increased NO production in both cell types, albeit to a larger extent in CMEC, 4) in hypoxic cardiomyocytes, nonselective NOS and iNOS-specific inhibition attenuated NO production, whereas in CMEC, iNOS-specific inhibition was ineffective, and 5) baseline ONOO- production was 2.2 times greater in CMEC than in cardiomyocytes. CONCLUSION: Using a novel approach, this study demonstrated that CMEC produce more baseline NO than cardiomyocytes, and that hypoxia activates NOS to increase NO production in both cell types. Baseline eNOS content was higher in CMEC than in cardiomyocytes, suggesting that differences in baseline NO production were eNOS-associated.
