fumarates and Hyperplasia

Excessive proliferation of vascular smooth muscle cells (VSMCs) and incomplete re-endothelialization is a major clinical problem limiting the long-term efficacy of percutaneous coronary angioplasty. We tested if dimethylfumarate (DMF), an anti-psoriasis drug, could inhibit abnormal vascular remodeling via NF-E2-related factor 2 (Nrf2)-NAD(P)H quinone oxidoreductase 1 (NQO1) activity. DMF significantly attenuated neointimal hyperplasia induced by balloon injury in rat carotid arteries via suppression of the G1 to S phase transition resulting from induction of p21 protein in VSMCs. Initially, DMF increased p21 protein stability through an enhancement in Nrf2 activity without an increase in p21 mRNA. Later on, DMF stimulated p21 mRNA expression through a process dependent on p53 activity. However, heme oxygenase-1 (HO-1) or NQO1 activity, well-known target genes induced by Nrf2, were dispensable for the DMF induction of p21 protein and the effect on the VSMC proliferation. Likewise, DMF protected endothelial cells from TNF-α-induced apoptosis and the dysfunction characterized by decreased eNOS expression. With knock-down of Nrf2 or NQO1, DMF failed to prevent TNF-α-induced cell apoptosis and decreased eNOS expression. Also, CD31 expression, an endothelial specific marker, was restored in vivo by DMF. In conclusion, DMF prevented abnormal proliferation in VSMCs by G1 cell cycle arrest via p21 upregulation driven by Nrf2 and p53 activity, and had a beneficial effect on TNF-α-induced apoptosis and dysfunction in endothelial cells through Nrf2-NQO1 activity suggesting that DMF might be a therapeutic drug for patients with vascular disease.

Topics: Animals; Apoptosis; Carotid Artery Injuries; Cell Proliferation; Cells, Cultured; Coronary Restenosis; Dimethyl Fumarate; Fumarates; G1 Phase Cell Cycle Checkpoints; Heme Oxygenase-1; Humans; Hyperplasia; Immunosuppressive Agents; Male; Muscle, Smooth, Vascular; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Up-Regulation

Data on a protective role of fumarate in acute ischemia of the rat heart led to the obvious hypothesis that addition of fumarate to the preservation solution for kidney transplantation may have beneficial value. This study was designed to test this hypothesis. Kidneys of Lewis or Fischer 344 rats were flushed with University of Wisconsin (UW) solution or UW solution containing 5 mM fumarate. Grafts were immediately transplanted to Lewis recipients or stored at 4 °C for 5 h before transplantation. Renal function was assessed on d 10 and monthly for 6 mo. One group of isografts was removed on d 10 post-transplantation, the other groups of isografts and allografts after 6 mo. We detected a modest protective effect regarding proteinuria 10 d after isogeneic transplantation, and exclude the possibility that fumarate exerts acute nephrotoxicity. Surprisingly, fumarate strongly promoted intimal hyperplasia of allograft arteries, thickening of the arterial media of isografts and allografts, tubulo-interstitial allograft damage, and allograft infiltration by macrophages on the long run. To date, we do not know the mechanism resulting in fumarate-induced chronic graft damage. We suggest, however, that addition of fumarate to the conservation fluid does not improve graft outcome.

Topics: Acute Disease; Animals; Chronic Disease; Fumarates; Hyperplasia; Kidney; Kidney Transplantation; Lactates; Leukocytes; Male; Organ Preservation Solutions; Primary Graft Dysfunction; Rats; Rats, Inbred F344; Rats, Inbred Lew; Renal Artery; Transplantation, Homologous

Fumaric acid (FA) was examined for its effect on hepatocarcinogenesis in rats fed 3-methyl-4'-(dimethylamino)azobenzene (3-Me-DAB). Male DONRYU rats were given approximately 0.5 g 3-Me-DAB by being fed a diet containing 0.06% 3-Me-DAB for 50 days; they were then given a diet containing 1% FA and drinking water containing 0.025% FA for 51 weeks. The administration of FA effectively suppressed the development of hepatocellular carcinoma, hyperplastic nodules, and hyperplastic areas in the livers of rats fed 3-Me-DAB.

Topics: Animals; Diet; Drug Interactions; Fumarates; Hyperplasia; Liver; Liver Neoplasms; Male; Methyldimethylaminoazobenzene; p-Dimethylaminoazobenzene; Rats

Topics: Animals; Appetite Depressants; Fumarates; Humans; Hyperplasia; Hypertension, Pulmonary; Hypertrophy; Oxazoles; Pulmonary Artery; Rats

Topics: Appetite Depressants; Dilatation; Fumarates; Humans; Hyperplasia; Hypertension, Pulmonary; Hypertrophy; Necrosis; Oxazoles; Pulmonary Artery