Heme oxygenase and carbon monoxide: Regulatory roles in islet hormone release - A biochemical, immunohistochemical, and confocal microscopic study

Carbon monoxide (CO) has been suggested as a novel messenger molecule in th e brain. We now report on the cellular localization and hormone secretory f unction of a GO-producing constitutive heme oxygenase. (HO-2) in mouse isle ts, Islet homogenates produced large amounts of CO which were suppressed do se-dependently by the HU inhibitor zincprotoporphyrin-IX (ZnPP-IX). We also show for the first time, that glucose markedly stimulates the HO activity (CO production) in intact islets, A further potentiation was induced by the HO substrate hemin. Western blot showed that islet tissue expressed HO-2, and confocal microscopy revealed that HO-2 resided in insulin, glucagon, so matostatin, and pancreatic polypeptide cells. ZnPP-IX dose-dependently inhi bited? whereas hemin enhanced, both insulin and glucagon secretion fi om gl ucose-stimulated islets, Stimulation or inhibition of CO production was acc ompanied by corresponding changes fn islet cGMP levels. Exogenously applied CO stimulated insulin and glucagon release from isolated Islets, whereas e xogenous nitric oxide (NO) inhibited insulin and stimulated glucagon releas e, Islets stimulated by glucose or L-arginine displayed a marked increase i n their NO-synthase (NOS) activity Such an increase was suppressed by hemin , conceivably because NOS activity was inhibited by hemin-derived CO, Conse quently, hemin enhanced L-arginine-induced insulin secretion, Insulin relea se stimulated by either hemin-derived CO or exogenous Cf) was strongly inhi bited try the guanylate cyclase inhibitor ODQ, but it was unaffected by ZnP P-IX, Glucagon release induced by CO (but not by hemin) was inhibited by OD Q and partly inhibited by ZnPP-IX. We propose that the islets of Langerhans are equipped with a heme oxygenase-carbon monoxide pathway which constitut es a novel regulatory system of physiological importance for the stimulatio n of insulin and glucagon release,This pathway is stimulated by glucose, is at least partly dependent on the cGMP system, and displays Interaction wit h islet NOS activity.