15d-PGJ2 stimulates HO-1 expression through p38 MAP kinase and Nrf-2 pathway in rat vascular smooth muscle cells.

15d-PGJ(2), a potent endogenous ligand for peroxisome proliferators activated receptor-gamma, is a cyclopentenone-type prostaglandin produced by many different types of cells. Pertinent to its effect on vascular smooth muscle cell (VSMC), antiproliferative effects have been most frequently reported. In the present study, we investigated the effect of 15d-PGJ(2) on HO-1 expression that has been reported to inhibit VSMC proliferation. According to our data, 15d-PGJ(2) significantly induced ROS/NO production and HO-1 expression in rVSMCs. We also observed 15d-PGJ(2)-induced translocation of Nrf-2. In addition, ROS scavenger pretreatment suppressed 15d-PGJ(2)-induced HO-1 expression while PPARgamma antagonist did not, suggesting nuclear translocation of Nrf-2 and subsequent HO-1 expression was ROS dependent rather than PPARgamma dependent. Furthermore, an inhibitor of p38 MAPK abolished 15d-PGJ(2)-induced HO-1 expression. These data suggest that 15d-PGJ(2)-induced up-regulation of HO-1 is independent of PPARgamma but dependent of ROS and p38 MAPK pathway. The present study reports for the first time that 15d-PGJ(2) induces HO-1 expression possibly using Nrf-2 pathway as a response to ROS in VSMCs.

Preconditioning with low concentration NO attenuates subsequent NO-induced apoptosis in vascular smooth muscle cells via HO-1-dependent mitochondrial death pathway.

Nitric oxide (NO) signaling pathways are important in both the maintenance of vascular homeostasis and disease progression. Overproduction of NO has been associated with ischemia/reperfusion (I/R) injury. Growing evidences suggest that NO preconditioning has cytoprotective effects against I/R injury. However, the mechanism with which NO mediates these effects remains to be elucidated. The purpose of this study was to examine the mechanism of how NO preconditioning inhibits subsequent NO-induced apoptosis in vascular smooth muscle cells (VSMC), specifically focusing on heme oxygenase-1 (HO-1). According to our data, sodium nitroprusside (SNP) increased HO-1 expression in a concentration dependent manner. Preconditioning with low concentration SNP (0.3mM) inhibited subsequent high concentration SNP (1.5mM)-induced apoptosis, and this effect was reversed by the HO-1 inhibitor SnPP. Low concentration SNP-mediated protection involved p38 kinase inactivation and increased Bcl-2 expression. Furthermore, mitochondrial membrane potential was concomitantly increased with decreased expressions of Bax, Apaf-1, and activity of caspase-3, which was reversed by SnPP treatment. Our results show that low concentration SNP preconditioning suppresses subsequent high concentration SNP-induced apoptosis by inhibiting p38 kinase and mitochondrial death pathway via HO-1-dependent mechanisms in VSMC.

Downregulation of neurotrophic factors in the brain of a mouse model of Gaucher disease; implications for neuronal loss in Gaucher disease.

Gaucher disease is a glycosphingolipid storage disease caused by deficiency of glucocerebrosidase, resulting in the accumulation of glucosylceramide in lysosomes. The neuronopathic forms of this disease are associated with neuronal loss and neurodegeneration. However, the pathophysiological mechanisms leading to prenatal and neonatal death remain uncharacterized. To investigate brain dysfunction in Gaucher disease, we studied the effects of neurotrophic factors during development in a mouse model of Gaucher disease. The expression of brain-derived neurotrophic factor and nerve growth factor was reduced in the cerebral cortex, brainstem, and cerebellum of Gaucher mice, compared with that in wild-type mice. Extracellular signal-regulated kinase (ERK) 1/2 expression was downregulated in neurons from Gaucher mice and correlated with a decreased number of neurons. These results suggest that a reduction in neurotrophic factors could be involved in neuronal loss in Gaucher disease.