Carbon Monoxide Differentially Modulates STAT1 and STAT3 and Inhibits Apoptosis via a Phosphatidylinositol 3-Kinase/Akt and p38 Kinase-dependent STAT3 Pathway during Anoxia-Reoxygenation Injury

Abstract

Carbon monoxide (CO), previously considered a toxic waste product of heme catabolism, is emerging as an important gaseous molecule. In addition to its important role in neurotransmission, exogenous CO protects against vascular injury, transplant rejection, and acute lung injury. However, little is known regarding the precise signaling mechanisms of CO. We have recently shown that CO attenuates endothelial cell apoptosis during anoxia-reoxygenation injury by activating MKK3/p38␣ mitogen-activated protein kinase (MAPK) pathways. Our current study is the first to demonstrate that CO can differentially modulate STAT1 and STAT3 activation and, specifically, that STAT3 activation by CO is responsible for the anti-apoptotic effect in endothelial cells. In addition, we show that the anti-apoptotic effects of CO depend upon both phosphatidylinositol 3-kinase/Akt and p38 MAPK signaling pathways in endothelial cells, whereas previous reports have implicated only the MKK3/p38 MAPK pathway. Using chemical inhibitors and dominant negative constructs, we show that CO enhances STAT3 activation via phosphatidylinositol 3-kinase/Akt and p38 MAPK pathways with subsequent attenuation of Fas expression and caspase 3 activity. These data highlight the anti-apoptotic signaling mechanisms of CO and, importantly, delineate potential therapeutic strategies to prevent ischemiareperfusion or anoxia-reoxygenation injury in the vasculature.

Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway

“…Interestingly, the effects of HO-1 on Akt activity and cell survival in this colon cancer cell line were mimicked by exogenous bilirubin, analogous to our current findings in H9c2 cells exposed to hypoxia and reoxygenation. Others have reported that CO also protects against I/R injury by increasing Akt activity [35,36]. Thus Akt and HO-1 may function cooperatively in cellular protection by reciprocally enhancing each other activity through direct transcriptional and post-translational events, and indirectly via the by-products of heme degradation, bilirubin and CO.…”

“…The cytoprotective properties of HO-1 have traditionally been attributed to the by-products of heme degradation, namely bilirubin and carbon monoxide (CO). Indeed, within a narrow therapeutic range, these catalytic by-products exert powerful antioxidant [15,31], antiinflammatory [32] and anti-apoptotic effects [33][34][35], leading to reduced infarct size [16,17,[36][37]. However, emerging evidence, suggests that HO-1 may also exert cytoprotective effects, independent of heme breakdown [38] by interacting with survival signaling pathways such as PI3K-Akt and p38.…”

High-pressure carbon monoxide preserves rat kidney grafts from apoptosis and inflammation

“…CO has anti-inflammatory and anti-apoptotic effects and has attracted attention as a medical gas. 15 Zhang et al 16 demonstrated that the anti-apoptotic effects of CO involve both the PI3K/Akt and p38 MAPK signaling pathways in endothelial cells in an anoxia-reoxygenation injury model. Nakao and colleagues also demonstrated that lowconcentration CO inhalation provided protection against cold I/R injury in a rat kidney transplantation model.…”

Heme Oxygenase-1 Couples Activation of Mitochondrial Biogenesis to Anti-inflammatory Cytokine Expression

“…Nfe2l2 activates the xenobiotic defenses, glutathione synthesis (75), superoxide detoxification (42), and NRF1 (30). CO activates Akt/PKB, which inhibits caspase-dependent apoptosis (76), but also facilitates Nfe2l2 and NRF-1 nuclear translocation and hence mitochondrial biogenesis (30,47).…”