Protective effects of the thioredoxin and glutaredoxin systems in dopamine-induced cell death

Although the etiology of sporadic Parkinson disease (PD) is unknown, it is well established that oxidative stress plays an important role in the pathogenic mechanism. The thioredoxin (Trx) and glutaredoxin (Grx) systems are two central systems upholding the sulfhydryl homeostasis by reducing disulfides and mixed disulfides within the cell and thereby protecting against oxidative stress. By examining the expression of redox proteins in human postmortem PD brains, we found the levels of Trx1 and thioredoxin reductase 1 (TrxR1) to be significantly decreased. The human neuroblastoma cell line SH-SY5Y and the nematode Caenorhabditis elegans were used as model systems to explore the potential protective effects of the redox proteins against 6-hydroxydopamine (6-OHDA)-induced cytotoxicity. 6-OHDA is highly prone to oxidation, resulting in the formation of the quinone of 6-OHDA, a highly reactive species and powerful neurotoxin. Treatment of human cells with 6-OHDA resulted in an increased expression of Trx1, TrxR1, Grx1, and Grx2, and small interfering RNA for these genes significantly increased the cytotoxic effects exerted by the 6-OHDA neurotoxin. Evaluation of the dopaminergic neurons in C. elegans revealed that nematodes lacking trxr-1 were significantly more sensitive to 6-OHDA, with significantly increased neuronal degradation. Importantly, both the Trx and the Grx systems were also found to directly mediate reduction of the 6-OHDA-quinone in vitro and thus render its cytotoxic effects. In conclusion, our results suggest that the two redox systems are important for neuronal survival in dopamine-induced cell death. © 2014 Elsevier Inc.A.P.F. was supported by Stiftelsen Lars Hiertas Minne and Karolinska Institutet research grants. Research in the Swoboda laboratory was supported by the Swedish Research Council (VR) and the NordForsk Nordic network for C. elegans research. A.M.-V. was supported by the Instituto de Salud Carlos III (Projects PI050065 and PI080557, cofinanced by the Fondo Social Europeo, FEDER) and Junta de Andalucía (Projects P07-CVI-02697 and P08-CVI-03629), Spain. Some C. elegans strains were provided by the CGC, which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440).Peer Reviewe

Cardiac magnetic resonance left ventricular filling pressure is associated with NT-proBNP in patients with new onset heart failure

Background and Objectives: Cardiovascular magnetic resonance (CMR) is emerging as an important imaging tool for sub-phenotyping and estimating left ventricular (LV) filling pressure (LVFP). The N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) is released from cardiac myocytes in response to mechanical load and wall stress. This study sought to investigate if CMR-derived LVFP is associated with the serum levels of NT-proBNP and, in addition, if it provides any incremental prognostic value in heart failure (HF). Materials and Methods: This study recruited 380 patients diagnosed with HF who underwent same-day CMR and clinical assessment between February 2018 and January 2020. CMR-derived LVFP was calculated, as previously, from long- and short-axis cines. During CMR assessment, serum NT-proBNP was measured. The pathological cut-offs were defined as follows: NT-proBNP ≥ 125 pg/mL and CMR LVFP > 15 mmHg. The incidence of HF hospitalisation was treated as a clinical outcome. Results: In total, 305 patients had NT-proBNP ≥ 125 pg/mL. Patients with raised NT-proBNP were older (54 ± 14 vs. 64 ± 11 years, p < 0.0001). Patients with raised NT-proBNP had higher LV volumes and mass. In addition, CMR LVFP was higher in patients with raised NT-proBNP (13.2 ± 2.6 vs. 15.4 ± 3.2 mmHg, p < 0.0001). The serum levels of NT-proBNP were associated with CMR-derived LVFP (R = 0.42, p < 0.0001). In logistic regression analysis, this association between NT-proBNP and CMR LVFP was independent of all other CMR variables, including LV ejection fraction, LV mass, and left atrial volume (coefficient = 2.02, p = 0.002). CMR LVFP demonstrated an independent association with the incidence of HF hospitalisation above NT-proBNP (hazard ratio 2.7, 95% confidence interval 1.2 to 6, p = 0.01). Conclusions: A CMR-modelled LVFP is independently associated with serum NT-proBNP levels. Importantly, it provides an incremental prognostic value over and above serum NT-proBNP levels