Dimethyl fumarate, a small molecule drug for psoriasis, inhibits Nuclear Factor-kappaB and reduces myocardial infarct size in rats.
Persistent Nuclear Factor-kappaB (NF-kappaB) activation is hypothesized to contribute to myocardial injuries following ischemia-reperfusion. Because inhibition or control of NF-kappaB signaling in the heart probably confers cardioprotection, we determined the potency of the NF-kappaB inhibitor dimethyl fumarate (DMF) in cardiovascular cells, and determined whether administration of DMF translates into beneficial effects in an animal model of myocardial infarction. In rat heart endothelial cells (RHEC), we analysed inhibitory effects of DMF on NF-kappaB using shift assay and immunohistofluorescence. In in vivo experiments, male Sprague Dawley rats undergoing left coronary artery occlusion for 45 min received either DMF (10 mg/kg body weight) or vehicle 90 min before ischemia as well as immediately before ischemia. After 120 min of reperfusion, the hearts were stained with phthalocyanine blue dye and triphenyltetrazolium chloride. Additionally, acute hemodynamic and electrophysiologic effects of DMF were determined in dose-response experiments in isolated perfused rat hearts. DMF inhibited TNF-alpha-induced nuclear entry of NF-kappaB in RHEC. In in vivo experiments, myocardial infarct size was significantly smaller in rats that had received DMF (20.7%+/-9.7% in % of risk area; n=17) than in control rats (28.2%+/-6.2%; n=15). Dose-response experiments in isolated perfused rat hearts excluded acute hemodynamic or electrophysiologic effects as mechanisms for the effects of DMF. DMF inhibits nuclear entry of NF-kappaB in RHEC and reduces myocardial infarct size after ischemia and reperfusion in rats in vivo. There was no indication that the beneficial effects of DMF were due to acute hemodynamic or electrophysiologic influences.
Meili-Butz
Silvia
S
University Hospital Basel, Department of Research, Cardiobiology Laboratories, Switzerland. Silvia.Meili@unibas.ch
Niermann
Thomas
T
Fasler-Kan
Elizaveta
E
Barbosa
Vania
V
Butz
Nicole
N
John
Dietlinde
D
Brink
Marijke
M
Buser
Peter T
PT
Zaugg
Christian E
CE
D000818:Animals; D003879:Dermatologic Agents / Q000627:therapeutic use*; D000069462:Dimethyl Fumarate; D004562:Electrocardiography / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D004594:Electrophysiology; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005455:Fluorescent Antibody Technique; D005650:Fumarates / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000473:pathology; D009206:Myocardium / Q000166:cytology / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009687:Nuclear Proteins / Q000378:metabolism; D011565:Psoriasis / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley
D003879:Dermatologic Agents; D005650:Fumarates; D016328:NF-kappa B; D009687:Nuclear Proteins; D000069462:Dimethyl Fumarate