HuR mediates the synergistic effects of angiotensin II and IL-1ß on vascular COX-2 expression and cell migration.

BACKGROUND AND PURPOSE: Angiotensin II (AngII) and IL-1ß are involved in cardiovascular diseases through the induction of inflammatory pathways. HuR is an adenylate- and uridylate-rich element (ARE)-binding protein involved in the mRNA stabilization of many genes. This study investigated the contribution of HuR to the increased expression of COX-2 induced by AngII and IL-1ß and its consequences on VSMC migration and remodelling. EXPERIMENTAL APPROACH: Rat and human VSMCs were stimulated with AngII (0.1 µM) and/or IL-1ß (10 ng · mL(-1)). Mice were infused with AngII or subjected to carotid artery ligation. mRNA and protein levels were assayed by quantitative PCR, Western blot, immunohistochemistry and immunofluorescence. Cell migration was measured by wound healing and transwell assays. KEY RESULTS: In VSMCs, AngII potentiated COX-2 and tenascin-C expressions and cell migration induced by IL-1ß. This effect of AngII on IL-1ß-induced COX-2 expression was accompanied by increased COX-2 3' untranslated region reporter activity and mRNA stability, mediated through cytoplasmic HuR translocation and COX-2 mRNA binding. These effects were blocked by ERK1/2 and HuR inhibitors. VSMC migration was reduced by blockade of ERK1/2, HuR, COX-2, TXAS, TP and EP receptors. HuR, COX-2, mPGES-1 and TXAS expressions were increased in AngII-infused mouse aortas and in carotid-ligated arteries. AngII-induced tenascin-C expression and vascular remodelling were abolished by celecoxib and by mPGES-1 deletion. CONCLUSIONS AND IMPLICATIONS: The synergistic induction of COX-2 by AngII and IL-1ß in VSMCs involves HuR through an ERK1/2-dependent mechanism. The HuR/COX-2 axis participates in cell migration and vascular damage. HuR might be a novel target to modulate vascular remodelling.

[Survival of grafts in the first 100 renal transplants at the Carlos van Buren Hospital]. / Sobrevida del injerto en los primeros 100 trasplantes renales del Hospital Carlos van Buren.

BACKGROUND: Renal transplant is the best therapeutic alternative for chronic renal failure, although it is not exempt of risks. AIM: To report the survival of renal transplant recipients and grafts and the main complications at a public hospital in Chile. PATIENTS AND METHODS: This is a non experimental, open historical cohort study, with reposition of the first 100 transplants in 94 patients, performed at the Carlos van Buren Hospital between 1984 and 1998. Seventy grafts came from cadaveric donors and 30 from live donors. As immunosuppressive therapy, prednisone + azathioprine was used in 48 transplants and the same regimen plus cyclosporine in 52. RESULTS: Mean age of recipients was 36 +/- 23 years old. Ten years actuarial survival of patients was 80.5% in transplants from cadaveric donors and 86% in transplants from live donors. Ten years graft survival was 57.5% in transplants from cadaveric donors and 42% in transplants from live donors. The period in which the transplant was performed (first or second half of the observation period), type of donor, HLA B-DR compatibility and sensitization (% PRA) had no effect on survival. Twenty five subjects lost their graft, 12 due to acute steroid resistant rejection, 10 due to chronic graft nephropathy and three due to renal artery thrombosis. Fifteen subjects died with a functioning graft, 10 due to infections, two due to an acute myocardial infarction, two due to an acute pancreatitis and one due to a brain tumor. CONCLUSIONS: Survival of grafts and renal transplant recipients was not influenced by the type of donor, period of transplantation and immune variables. Main causes of recipient death were infections and the main cause of graft failure was acute rejection.