Imidazoline compounds protect against interleukin 1beta-induced beta-cell apoptosis.
Imidazoline compounds have been considered for the treatment of type 2 diabetes. We have now investigated the effects of imidazolines on interleukin (IL)-1beta-induced beta-cell apoptosis and the signal transduction pathways involved. Inhibition of Ca2+ influx into beta-cells by D-600, a blocker of voltage-gated L-type Ca2+ channels, suppressed IL-1beta-induced apoptosis. Our data show that calcineurin, Ca2+/calmodulin-dependent serine/threonine protein phosphatase 2B, is responsible for the effect of Ca2+ on beta-cell apoptosis. We also demonstrate that IL-1beta-mediated apoptosis correlates with expression of inducible nitric oxide synthase (iNOS) and the increase in intracellular production of nitric oxide. An inhibitor of cGMP-dependent protein kinase (PKG), KT5823, suppressed IL-1beta-induced apoptosis, suggesting the involvement of a PKG-dependent pathway in the apoptotic process. One of the major findings in this study is that imidazoline compounds RX871024 and efaroxan, suggested as prototypes of a new generation of drugs against type 2 diabetes, can protect against IL-1beta-induced apoptosis in pancreatic beta-cells, possibly by their inhibition of the expression of iNOS, a key element in the IL-1beta-induced apoptotic pathway in pancreatic beta-cells. These data suggest that imidazoline compounds should be explored as a potential therapeutic agent for the treatment of both type 1 and type 2 diabetes.
Zaitsev
S V
SV
Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. sergei.zaitsev@enk.ks.se
Appelskog
I B
IB
Kapelioukh
I L
IL
Yang
S N
SN
Köhler
M
M
Efendic
S
S
Berggren
P O
PO
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001572:Benzofurans / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005711:Gallopamil / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008820:Mice, Obese; D008954:Models, Biological; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009570:Nitriles; D018408:Patch-Clamp Techniques; D011722:Pyrethrins / Q000494:pharmacology
C101943:2-(2-imidazolin-2-yl)-1-phenyl-1H-indole; D001572:Benzofurans; D065095:Calcineurin Inhibitors; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007211:Indoles; D007375:Interleukin-1; D009570:Nitriles; D011722:Pyrethrins; C017180:decamethrin; D005711:Gallopamil; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019703:Calcineurin; C062597:efaroxan; D019331:NG-Nitroarginine Methyl Ester