| First Author | Wang DZ | Year | 2016 |
| Journal | Am J Physiol Gastrointest Liver Physiol | Volume | 310 |
| Issue | 9 | Pages | G747-56 |
| PubMed ID | 26950856 | Mgi Jnum | J:234552 |
| Mgi Id | MGI:5790260 | Doi | 10.1152/ajpgi.00323.2015 |
| Citation | Wang DZ, et al. (2016) Soluble guanylate cyclase activation during ischemic injury in mice protects against postischemic inflammation at the mitochondrial level. Am J Physiol Gastrointest Liver Physiol 310(9):G747-56 |
| abstractText | The aim was to determine whether treatment with BAY 60-2770, a selective activator of oxidized soluble guanylate cyclase (sGC), near the end of an ischemic event would prevent postischemic inflammation and mitochondrial dysfunction in wild-type (WT) and heme oxygenase-1 KO (HO-1(-/-)) mice. This protocol prevented increases in leukocyte rolling (LR) and adhesion (LA) to intestinal venules along with elevated TNFalpha and circulating neutrophil levels that accompany ischemia-reperfusion (I/R) in both animal models. We further hypothesized that a component of BAY 60-2770 treatment involves maintenance of mitochondrial membrane integrity during I/R. Measurements on isolated enterocytes of calcein fluorescence (mitochondrial permeability) and JC-1 fluorescence ratio (mitochondrial membrane potential) were reduced by I/R, indicating formation of mitochondrial permeability transition pores (mPTP). These effects were abrogated by BAY 60-2770 as well as cyclosporin A and SB-216763, which prevented mPTP opening and inhibited glycogen synthase kinase-3beta (GSK-3beta), respectively. Western blots of WT and HO-1(-/-) enterocytes indicated that GSK-3beta phosphorylation on Ser(9) (inhibitory site) was reduced by half following I/R alone (increased GSK-3beta activity) and increased by one-third (reduced GSK-3beta activity) following BAY 60-2770. Other investigators have associated phosphorylation of the GSK-3beta substrate cyclophilin D (pCyPD) with mPTP formation. We observed a 60% increase in pCyPD after I/R, whereas BAY 60-2770 treatment of sham and I/R groups reduced pCyPD by about 20%. In conclusion, selective activation of oxidized sGC of WT and HO-1(-/-) during ischemia protects against I/R-induced inflammation and preserves mucosal integrity in part by reducing pCyPD production and mPTP formation. |
