Mitochondrial protective effects of PARP-inhibition in hypertension-induced myocardial remodeling and in stressed cardiomyocytes.

AIMS: During oxidative stress mitochondria become the main source of endogenous reactive oxygen species (ROS) production. In the present study, we aimed to clarify the effects of pharmacological PARP-1 inhibition on mitochondrial function and quality control processes. MAIN METHODS: L-2286, a quinazoline-derivative PARP inhibitor, protects against cardiovascular remodeling and heart failure by favorable modulation of signaling routes. We examined the effects of PARP-1 inhibition on mitochondrial quality control processes and function in vivo and in vitro. Spontaneously hypertensive rats (SHRs) were treated with L-2286 or placebo. In the in vitro model, 150 µM H2O2 stress was applied on neonatal rat cardiomyocytes (NRCM). KEY FINDINGS: PARP-inhibition prevented the development of left ventricular hypertrophy in SHRs. The interfibrillar mitochondrial network were less fragmented, the average mitochondrial size was bigger and showed higher cristae density compared to untreated SHRs. Dynamin related protein 1 (Drp1) translocation and therefore the fission of mitochondria was inhibited by L-2286 treatment. Moreover, L-2286 treatment increased the amount of fusion proteins (Opa1, Mfn2), thus preserving structural stability. PARP-inhibition also preserved the mitochondrial genome integrity. In addition, the mitochondrial biogenesis was also enhanced due to L-2286 treatment, leading to an overall increase in the ATP production and improvement in survival of stressed cells. SIGNIFICANCE: Our results suggest that the modulation of mitochondrial dynamics and biogenesis can be a promising therapeutical target in hypertension-induced myocardial remodeling and heart failure.

Haematopoietic stem cell transplantation in children in eastern European countries 1985-2004: development, recent activity and role of the EBMT/ESH Outreach Programme.

The paediatric population of 19 eastern European countries amounts to approximately 80 million children. Between 1985 and 2004, the number of centres performing haematopoietic stem cell transplantation (HSCT) in children increased from 1 in 1985 to 24 in 2004 and the yearly number of paediatric HSCTs rose from 1 in 1985 to 291 in 2004. Altogether, 2342 transplants were reported to the EBMT Registry during this time (Poland 953, Czech Republic 501, Hungary 269, Russia 217, Croatia 129, Slovakia 71, Bulgaria 45, Serbia and Montenegro 36, Slovenia 35, Belarus 33, Estonia 26, Lithuania 19 and Romania 8). Out of the 2342 transplants, 1487 (63.5%) transplants were performed in paediatric centres, 453 (19.3%) in centres for adults and 402 (17.2%) in combined centres. The number of children who underwent autologous HSCT (auto-HSCT) was 1053 (45%), whereas 1289 (55%) underwent allogeneic HSCT (allo-HSCT). Peripheral blood (PB) was the source of HSC in 751 (71.3%) out of 1053 auto-transplants, BM in 246 (23.4%) and PB+BM in 52 (4.9%) (missing data in 4, that is, 0.4%). Among the 1289 allo-transplants, BM was the source of HSC in 827 (64.3%), PB in 416 (32.3%), CB in 23 (1.8%) and BM+PB in 14 (1.1%) (missing data in 9, that is, 0.7%). Among them, 728 (57.4%) obtained HSC from MSD, 322 (25.4%) from UD, 195 (15.4%) from MMFD, 14 (1.1%) from CB family donor and 9 (0.7%) from CB unrelated donor (missing data in 21, that is, 1.6%). The number of children who underwent allo-HSCT for malignant diseases was 945 (73.4%), including ALL 376 (29.2%), AML 234 (18.2%), CML 177 (13.8%), MDS 97 (7.5%), NHL 35 (2.7%) and other malignancy 31 (2.4%), while 339 (26.9%) for non-malignant disorders, including SAA 202 (15.7%), immunodeficiencies 61 (4.7%), inborn errors of metabolism 40 (3.1%), Fanconi anaemia 19 (1.5%) and others 17 (1.3%). Out of 1053 recipients of auto-HSCT, 168 (16%) were transplanted for neuroblastoma, 129 (12.2%) for NHL, 124 (11.7%) for AML, 114 (10.8%) for ALL, 109 (10.4%) for Hodgkin's disease, 62 (5.9%) for Ewing's sarcoma, 16 (1.5%) for CNS tumour, 15 (1.4%) for Wilms tumour and 316 (30%) for other tumours. In 2001, the EBMT in collaboration with the European School of Haematology (ESH) developed the Outreach Programme, that is a programme supporting emerging HSCT projects and transplant centres in countries with limited resources and/or experience.