Cytoprotective Mechanisms of DJ-1: Implications in Cardiac Pathophysiology

Figure 1. Schematic diagram of the various pathways regulated by DJ-1. Representation of the different DJ-1 activation pathways. DJ-1 possesses chaperone and protease activities and regulates pathways involved in cell death, ROS production, autophagy, cell division, and inflammation.

Figure 2. Polymorphonuclear cell DJ-1 expression is increased in septic patients and inversely correlates with the inflammatory cytokine ILA. Neutrophil RNA was isolated from healthy controls (n = 3) and septic patients (n = 8) using TRIzol reagent and reverse transcribed into cDNA. DJ-1, IL1A, and 18S (housekeeping) gene expression was determined by real-time quantitative (RT-PCR). The Human Ethics Review Committee of St. Michael’s Hospital reviewed and approved the ‘inflammation in trauma and sepsis’ (INSIST) study protocol for collecting blood from healthy volunteers and septic patients. Written informed consent was obtained from patients or a surrogate decision-maker. DJ-1/18S and 1L1A/18S mRNA expression in septic neutrophils was calculated as a log-fold change over healthy controls and presented as box plots showing the median and interquartile range (A). Negative correlation between pro-inflammatory IL1A and DJ-1 (B). Human septic neutrophils were transfected with a scrambled (control) or a caspase 8 (apical caspase in the extrinsic cell death pathway) siRNA for 24 h (C).

Figure 3. Lung DJ-1 expression is decreased in patients with pulmonary hypertension (PH). In a prospective study, 12 patients of whom 6 (4 male and 2 female; mean ± SEM age 59.8 ± 4.4 years) were cancer patients negative for lung malignancy with a pulmonary artery systolic pressure <25 mmHg and 6 (4 male and 2 female; mean age 64.5 ± 3.1 years) with thromboembolic pulmonary hypertension negative for malignancy with a mean ± SEM pulmonary artery systolic pressure of 70 ± 4 mmHg. The lung biopsies were taken from the left lower lobe by video-assisted thoracic surgery. The pulmonary artery systolic pressure was assessed using echocardiography measuring maximal tricuspid regurgitation velocity and applying the modified Bernoulli equation to convert this value into pressure. The study was approved by the ethics committee of the University of Athens General Hospital Attikon, and informed consent was obtained from all patients. DJ-1, BCL2, and 18S (housekeeping) gene expression in the lung was determined by real-time quantitative (RT-PCR). DJ-1/18S mRNA in PH was calculated as a fold change over healthy and presented as box plots showing the median and interquartile range. p value shown (A).…

Figure 4. Aortic wall DJ-1 expression is decreased in patients with ascending thoracic aneurism. In a prospective study, 66 consecutive patients of whom 31 (18 male and 13 female; mean age 64.6 ± 11.5 years) with normal ascending thoracic aortic diameter underwent atrial valve replacement for severe aortic valve stenosis (AVS), and 35 patients (28 male and 7 female; mean age 65 ± 10.2 years) underwent replacement of an ascending thoracic aortic aneurysm (ATAA). The study was approved by the ethics committee of the University of Athens General Hospital Attikon, and informed consent was obtained from all patients. Biopsy-sized pieces of the aortic wall were collected from the greater curvature of the distal aortic root neighboring the anterolateral portion of the sino-tubular junction (ATAA). DJ-1, BAX, and 18S (housekeeping) gene expression was determined by real-time quantitative (RT-PCR). DJ-1/18S mRNA in ATAA was calculated as fold change over AVS and presented as box plots showing the median and interquartile range. p value shown (A). Negative correlation between pro-apoptotic BAX and DJ-1 in ATAA patients (B).

Figure 5. Right atrial appendage (RAA) DJ-1 mRNA is increased post-on and -off CABG specifically in off-pump patients that remain in sinus rhythm (SR). This prospective study examined 67 patients (44 males and 23 females, mean age 64.1 ± 1.13 years) that underwent elective on-pump coronary artery bypass grafting (CABG) and 31 patients (28 male and 3 females, mean age 64.1 ± 1.53 years) that underwent elective off-pump surgery. Inclusion criteria were as follows: (1) preoperative SR; (2) elective CABG. Exclusion criteria were as follows: (1) history of AF/flutter; (2) history of prior cardiac surgery; and any antiarrhythmic medication pre or peri-operatively. Post-operative atrial fibrillation (POAF) was based on the documentation of AF episodes (>30 s) by continuous ECG monitoring up to 7 days after surgery. The study was approved by the ethics committee of the University of Athens General Hospital Attikon, and informed consent was obtained from all patients. RAA was obtained from the same location pre and post CABG. DJ-1 and 18S (housekeeping) gene expression was determined by real-time quantitative (RT-PCR). RAA DJ-1/18S mRNA is represented as a fold change versus pre-CABG (A,B) and…

Figure 6. Schematic of DJ-1’s potential role in sepsis and cardiovascular disease. Our data are summarized in this schematic diagram. In innate immune cells, following an inflammatory or bacterial stimulus, DJ-1 expression is increased. Available DJ-1 can regulate bactericidal activity by directly scavenging superoxide ions and reducing ROS. Alternatively, in the redox state, DJ-1 may bind to p47phox and disrupt NADPH oxidase complex assembly, or ubiquitinate NADPH oxidase, subsequently leading to decreased ROS production (A). In response to an increase in oxidative stress, DJ-1 can exert antioxidant function by upregulating Nrf2 activation and downregulating pro-apoptotic Dax and Ask1 (B). Nrf2, NF-E2 related factor-2; ASK1, apoptosis signal-regulating kinase 1; Daxx, death-associated protein 6.