Angiotensin II increases superoxide production in human arteries

Background: Increased vascular superoxide (O2 -) production contributes to endothelial dysfunction and vascular hypertrophy. We investigated whether, and by what mechanisms, angiotensin II (AII) might increase O2 - production in blood vessels. Methods: Internal mammary arteries (IMA) and saphenous veins (SV) were collected from patients undergoing coronary revascularisation surgery. Five mm rings were incubated in the absence (control) or presence 1 μmol/L of AII, or 1 μmol/L of norepinephrine (NE, positive control) for 4 hours. All-incubated rings were co-incubated with an NADH oxidase inhibitor, diphenyleneiodonium (DPI, 100 μmol/L) or a specific All type 1 (AT1) receptor antagonist, losartan (1 μmol/L). O2 - production was measured by lucigenin chemiluminescence. Identification of NADH oxidase within IMA and SV was undertaken using specific antibodies to its active subunits (p22 and p91 phox). Results: All increased O2 - production in IMA (control=978±117 pmol/min/mg, AII 1690±213 pmol/min/mg; n=27, p<0.0001) but not in SV (n=8). NE had no effect on O2 - production in either IMA (control 731±323 pmol/min/mg, NE 636±241; n=10, p=0.76), or SV (n=8). Losartan blocked the AII-mediated increase of O2 - production (losartan 947±245 pmol/min/mg, losartan + AII 1037±231 pmol/min/mg; n=11, p=0.15). DPI inhibited the AII mediated increase in O2 - production (DPI 1124±338 pmol/min/mg, AII + DPI 1055±146 pmol/min/mg; n=8, p=0.9). P22 and p91 phox proteins were localised principally within vascular smooth muscle cells. Conclusion: All increases O2 - production in human arteries by an AT1 receptor-specific, NADH oxidase-dependent mechanism. This suggests a novel therapeutic role for AT1 receptor antagonists in reducing oxidative stress in patients with cardiovascular disease

Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan

Changes in the rate and fidelity of mitochondrial protein synthesis impact the metabolic and physiological roles of mitochondria. Here we explored how environmental stress in the form of a high-fat diet modulates mitochondrial translation and affects lifespan in mutant mice with error-prone (Mrps12ep/ep) or hyper-accurate (Mrps12ha/ha) mitochondrial ribosomes. Intriguingly, although both mutations are metabolically beneficial in reducing body weight, decreasing circulating insulin and increasing glucose tolerance during a high-fat diet, they manifest divergent (either deleterious or beneficial) outcomes in a tissue-specific manner. In two distinct organs that are commonly affected by the metabolic disease, the heart and the liver, Mrps12ep/ep mice were protected against heart defects but sensitive towards lipid accumulation in the liver, activating genes involved in steroid and amino acid metabolism. In contrast, enhanced translational accuracy in Mrps12ha/ha mice protected the liver from a high-fat diet through activation of liver proliferation programs, but enhanced the development of severe hypertrophic cardiomyopathy and led to reduced lifespan. These findings reflect the complex transcriptional and cell signalling responses that differ between post-mitotic (heart) and highly proliferative (liver) tissues. We show trade-offs between the rate and fidelity of mitochondrial protein synthesis dictate tissue-specific outcomes due to commonly encountered stressful environmental conditions or aging

Tumour necrosis factor (TNF-alpha) and neurological disorders in HIV infection.

Tumour necrosis factor (TNF-alpha) concentrations were determined in the CSF from 42 HIV-infected patients, with or without CNS involvement. In addition, 14 subjects with various neurological disorders but without HIV antibodies were included as controls. Raised CSF concentrations of TNF-alpha (greater than 40 ng/l) were detected both in patients with AIDS dementia complex (ADC) (6/9) and with CNS opportunistic infections (10/19) and, less commonly, in HIV infected subjects without CNS diseases (2/14) and in anti-HIV negative controls (1/14). The highest CSF concentrations of TNF-alpha (greater than 100 ng/l), however, were found in seven out of eight patients with cryptococcal meningitis. Although a role for TNF-alpha in demyelinating lesions associated with ADC has been suggested, our results indicate that a clear elevation of TNF-alpha in the CSF from HIV positive patients mostly occurs in acute inflammatory disorders, such as cryptococcal meningitis

Telomere alterations in neurofibromatosis type 1-associated solid tumors

The presence of Alternative lengthening of telomeres (ALT) and/or ATRX loss, as well as the role of other telomere abnormalities, have not been formally studied across the spectrum of NF1-associated solid tumors. Utilizing a telomere-specific FISH assay, we classified tumors as either ALT-positive or having long (without ALT), short, or normal telomere lengths. A total of 426 tumors from 256 NF1 patients were evaluated, as well as 99 MPNST tumor samples that were sporadic or of unknown NF1 status. In the NF1-glioma dataset, ALT was present in the majority of high-grade gliomas: 14 (of 23; 60%) in contrast to only 9 (of 47; 19%) low-grade gliomas (p\u2009=\u20090.0009). In the subset of ALT-negative glioma cases, telomere lengths were estimated and we observed 17 (57%) cases with normal, 12 (40%) cases with abnormally long, and only 1 (3%) case with short telomeres. In the NF1-associated malignant nerve sheath tumor (NF1-MPNST) set (n\u2009=\u200975), ALT was present in 9 (12%). In the subset of ALT-negative NF1-MPNST cases, telomeres were short in 9 (38%), normal in 14 (58%) and long in 1 (3%). In the glioma set, overall survival was significantly decreased for patients with ALT-positive tumors (p\u2009<\u20090.0001). In the NF1-MPNST group, overall survival was superior for patients with tumors with short telomeres (p\u2009=\u20090.003). ALT occurs in a subset of NF1-associated solid tumors and is usually restricted to malignant subsets. In contrast, alterations in telomere lengths are more prevalent than ALT