5-Aminosalicylic Acid Modulate The Remodeling Of Pulmonary Vascular Endothelial Cells Via The Orphan Nuclear Receptor Nur77

Part? 5-aminosalicylic acid improve the pulmonary hemodynamics in monocrotaline-induced pulmonary arterial hypertension ratsObjective: To investigate the effects of 5-aminosalicylic acid on monocrotaline-induced pulmonary arterial hypertension in rats.Methods: 60 Sprague-Dawley rats were randomly divided into six groups with each for 10: normal control group(Control group), untreated pulmonary arterial hypertension group(PAH group) and various 5-aminosalicylic acid-dosage treated pulmonary arterial hypertension group(5ASA-50, 5ASA-100, 5ASA-150, 5ASA-200) after monocrotaline injection by 30 days' gavage. The PAH was induced by intraperitoneal injection of 50 mg/kg monocrotaline on day 1. And the rats in the Control group were injected with isovolumetric normal saline. From day 2, 5-ASA group were treated with different dosage: 5-ASA 50, 100, 150, 200 mg·kg-1·d-1. On day 32, results were measured as following:(1). Body mass, weight increment and survival rates were measured.(2). Right heart catheter was used to measure pulmonary hemodynamics(SPAP, DPAP, and MPAP).(3). The right ventricle(RV) was separated from the left ventricle(LV) and septum(S), and weighed to determine the RVHI.Results:(1). Compared with PAH group, body mass and weight increment in Control group were significantly increased(P < 0.05). After 30 days' treatment, except 5ASA-150 group and 5ASA-200 group, other 5-ASA treatment group had a significant increase of body mass and weight increment compared with PAH group(P < 0.05). Survival rates in overall 5-ASA treatment group were significantly increased compared with PAH group(P < 0.05).(2). Expect MPAP and RVHI in 5ASA-200 group, SPAP, DPAP, MPAP and RVHI in other 5-ASA treatment group were significantly decreased than those in PAH group(P < 0.05, respectively).Conclusions: 5-ASA could reduce pulmonary arterial pressure and attenuate right heart ventricular hypertrophy and improve survival rates in monocrotaline-induced pulmonary arterial hypertension rats.Part? The orphan nuclear receptor Nur77 modulate apoptosis and proliferation of pulmonary vascular endothelial cellsObjective: To investigate the effect Nur77 on the apoptosis and proliferation of pulmonary vascular endothelial cells and to study the underlying mechanisms involved in expression of Nur77.Methods: 5-ASA was administrated to improve pulmonary hemodynamics in the MCT-induced PAH rat model. Western Blot, RT-PCR and immunofluorescence were used to detect the expression of Nur77 in pulmonary arterial endothelial cells. The proliferation of pulmonary arterial endothelial cells was detected by Hematoxylin and eosin staining. Inflammatory mediators(NF-?Bp65, I?B?, COX-2 and iNOS), apoptosis-related proteins(Bcl-2 and caspase-3), proliferation-related proteins(PCNA, MMP-2/-9 and TIMP-1/-2), signaling pathway proteins(pAkt, pERK and p-p38 MAPK) were tested by Western Blot and/or RT-PCR.Results:(1). Compared with PAH group, the expression of Nur77 in the pulmonary vascular endothelial cells had a significant increase in 5-ASA treatment group and Control group(P < 0.05).(2). Inflammatory mediators(NF-?Bp65, COX-2, iNOS), apoptosis inhibitory protein(Bcl-2), MMP-2/-9, and signaling pathway proteins(p Akt, p ERK and p-p38 MAPK) in the pulmonary vascular endothelial cells were decreased significantly in 5-ASA treatment group and Control group than those in PAH group(P < 0.05).(3). The expression of I?B?, caspase-3 and TIMP-1/-2 in 5-ASA treatment group and Control group had a significant increase than those in PAH group(P < 0.05).Conclusions:(1). 5-ASA had an effect of anti-inflammatory, anti-proliferative and pro-apoptotic via orphan nuclear receptor Nur77.(2). pAkt, pERK and p-p38 MAPK were involved to regulate the expression of of Nur77.(3). Nur77 modulate the balance of NF-?B/I?B? to restrain proliferation and promote apoptosis of pulmonary vascular endothelial cells.