Abstract
Carbon monoxide (CO) produced by heme oxygenase (HO)-1 and HO-2 or released from the CO-donor, tricarbonyldichlororuthenium (II) dimer (CORM-2) causes vasodilation, with unknown efficacy against stress-induced gastric lesions. We studied whether pretreatment with CORM-2 (0.1–10 mg/kg oral gavage (i.g.)), RuCl3 (1 mg/kg i.g.), zinc protoporphyrin IX (ZnPP) (10 mg/kg intraperitoneally (i.p.)), hemin (1–10 mg/kg i.g.) and CORM-2 (1 mg/kg i.g.) combined with NG-nitro-l-arginine (l-NNA, 20 mg/kg i.p.), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 mg/kg i.p.), indomethacin (5 mg/kg i.p.), SC-560 (5 mg/kg i.g.), and celecoxib (10 mg/kg i.g.) affects gastric lesions following 3.5 h of water immersion and restraint stress (WRS). Gastric blood flow (GBF), the number of gastric lesions and gastric CO and nitric oxide (NO) contents, blood carboxyhemoglobin (COHb) level and the gastric expression of HO-1, HO-2, hypoxia inducible factor 1α (HIF-1α), tumor necrosis factor α (TNF-α), cyclooxygenase (COX)-2 and inducible NO synthase (iNOS) were determined. CORM-2 (1 mg/kg i.g.) and hemin (10 mg/kg i.g.) significantly decreased WRS lesions while increasing GBF, however, RuCl3 was ineffective. The impact of CORM-2 was reversed by ZnPP, ODQ, indomethacin, SC-560 and celecoxib, but not by l-NNA. CORM-2 decreased NO and increased HO-1 expression and CO and COHb content, downregulated HIF-1α, as well as WRS-elevated COX-2 and iNOS mRNAs. Gastroprotection by CORM-2 and HO depends upon CO’s hyperemic and anti-inflammatory properties, but is independent of NO.
Highlights
Carbon monoxide (CO), previously regarded as a metabolic waste, is considered as a gaseous molecule exerting important signaling functions in the body [1,2]
We aimed to investigate other important factors involved in the mechanism of gastric protection such as soluble guanylyl cyclase (sGC)/cGMP, nitric oxide (NO)/NO synthase (NOS) and PG/COX systems by measuring both NO content in gastric tissues and changes in the mRNA expression of heme oxygenase (HO)-1, HO-2, hypoxia inducible factor 1α (HIF-1α) and pro-inflammatory factors tumor necrosis factor α (TNF-α), COX-2 and inducible NO synthase (iNOS) in gastric mucosa following water immersion and restraint stress (WRS)
CO-releasing molecules (CORMs)-2 (1 mg/kg i.g.) or hemin, administered in protective dose of 10 mg/kg did not produce the same results. This finding implies that the gastroprotective mechanism of CORM-2 against WRS damage involves the upregulation of HO-1 but not the HO-2, and that CO derived from HO-1 can compensate for the decrease in HO-2 expression in stressed gastric mucosa
Summary
Carbon monoxide (CO), previously regarded as a metabolic waste, is considered as a gaseous molecule exerting important signaling functions in the body [1,2]. CO can be produced by the actions of two microsomal proteins: induced by stress, heme oxygenase (HO)-1 and the constitutively expressed isoform, HO-2 [3]. Sensing gaseous molecules such as oxygen (O2), nitric oxide (NO) and CO are distinctive features of living organisms and are predominantly mediated by heme-based sensors [4]. Activity of iNOS can be directly inhibited by CO, which is known to bind to the heme moiety of the enzyme [16,17,18] Both cyclooxygenase (COX) isoforms, COX-1 and COX-2 are hemoproteins, which remain potential targets of CO [19,20]. Due to spectral similarities of heme-HO complex and both ferric myoglobin and Hb, HO seems to be another notable target of CO [22,23]
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