Carbon Monoxide Protects Against Cardiac Ischemia—Reperfusion Injury In Vivo via MAPK and Akt—eNOS Pathways

Fujimoto, Hajime; Ohno, Minoru; Ayabe, Seiji; Kobayashi, Hill Hiroki; Ishizaka, Nobukazu; Kimura, Hiroko; Yoshida, Kenichi; Nagai, Ryozo

doi:10.1161/01.atv.0000142364.85911.0e

Cited by 138 publications

(124 citation statements)

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“…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.…”

Section: Discussionmentioning

confidence: 98%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Pachori

Smith

McDonald

et al. 2007

Journal of Molecular and Cellular Cardiology

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Heme-oxygenase-1 (HO-1), a stress-inducible protein, is an important cytoprotective agent in various models of ischemia/reperfusion (I/R) injury. However, the role of downstream mediators involved in HO-1 induced cytoprotection is not clear. In the current study we investigated the role of biliverdin reductase, an enzyme involved in the conversion of HO-1 derived biliverdin into bilirubin and the PI3K/Akt pathway in mediating the cytoprotective effects of HO-1 against hypoxia and reoxygenation (H/R) injury in vitro and in vivo. H9c2 cardiomyocytes were transfected with a plasmid expressing HO-1 or LacZ and exposed to 24 hours of hypoxia followed by 12 hours of reoxygenation. At the end of reoxygenation, reactive oxygen species generation was determined using CM-H 2 DCFDA dye and apoptosis was assessed by TUNEL, caspase activity and Bad phosphorylation. p85 and Akt phosphorylation were determined using cell based ELISA and phospho-specific antibodies, respectively. HO-1 overexpression increased phosphorylation of the regulatory subunit of the PI3K (p85α) and downstream effector Akt in H9c2 cells, leading to decreased ROS and apoptosis. Furthermore, cardiac specific HO-1 expression increased basal phosphorylated Akt levels and decreased infarct size in response to LAD ligation and release induced I/R injury. Conversely, PI3K inhibition reversed the effects of HO-1 on Akt phosphorylation, cell death and infarct size. In addition, knockdown of biliverdin reductase (BVR) expression with siRNA attenuated HO-1 induced Akt phosphorylation and increased H/R-induced apoptosis of H9c2 cells. Co-immunoprecipitation revealed protein-protein interaction between BVR and the phosphorylated p85 subunit of the PI3 kinase. Taken together, these results suggest that the enzyme biliverdin reductase plays an important role in mediating cytoprotective effects of HO-1. This effect is mediated, at least in part, via activation of the PI3K/Akt pathway.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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

Pachori

Smith

McDonald

et al. 2007

Journal of Molecular and Cellular Cardiology

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“…In virtually all of the in vivo studies reported thus far, animals have been exposed to a CO concentration of Ͼ250 ppm for several hours or days before a stressful condition. 10,17,18 These studies showed that the levels of COHb rose to Ϸ20% after 250-ppm CO exposure. Therefore, we performed all of our experiments with CO at 60 ppm.…”

Section: Discussionmentioning

confidence: 97%

“…With this model, we examined the effects of low-dose exogenous CO administration. Different from conventional CO exposure conditions at 250 to 1000 ppm 3,10,17,18 that clinically induce CO intoxication, we used a lower and shorter-time CO exposing condition at 60 ppm for 2 hours daily. This clinically applicable CO treatment significantly attenuated Ang II-induced hypertension and cardiac and aortic hypertrophic responses accompanied with reduced ROS accumulation in these tissues.…”

Section: Discussionmentioning

confidence: 99%

Synergetic Antioxidant and Vasodilatory Action of Carbon Monoxide in Angiotensin II–Induced Cardiac Hypertrophy

et al. 2007

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Abstract-The aim of this study was to determine the effects of carbon monoxide (CO) at a nontoxic low concentration on the cardiac and vascular hypertrophic response and reactive oxygen species generation, compared with the action of a vasodilator, hydralazine. Twelve-to 16-week-old low-density lipoprotein receptor knockout mice were subjected to angiotensin II (Ang II) infusion using osmotic minipumps (Ang II group; nϭ11) for 2 weeks. Controls were administered saline (nϭ10). Animals were exposed to CO in a chamber at 60 ppm for 2 hours per day with or without Ang II infusion (Ang IIϩCO group, nϭ10; CO group, nϭ9). Hydralazine was administered with Ang II infusion (nϭ10). Animals exhibited elevated arterial carboxyhemoglobin after CO exposure. Although the CO exposure did not affect systolic blood pressure without Ang II infusion, the hypertensive response after Ang II infusion was significantly attenuated by CO. Accordingly, the mice in the Ang IIϩCO group showed lesser left ventricular hypertrophy compared with those in the Ang II group. CO treatment also attenuated aortic hypertrophy. Interestingly, these changes were accompanied by the reduction of reactive oxygen species production, p47 phox and p67 phox subunit expressions of reduced nicotinamide-adenine dinucleotide phosphate oxidase, and Akt phosphorylation. Although hydralazine showed stronger antihypertensive action, superior inhibition on cardiac hypertrophy was obtained by CO (PϽ0.05). Furthermore, Ang IIdependent myocardial reactive oxygen species generation was more effectively suppressed by CO. Low-dose exogenous CO treatment attenuates Ang II-dependent reactive oxygen species generation, suggesting that appropriate CO administration alleviates hypertension and reduces organ hypertrophy mediated by Ang II. Key Words: carbon monoxide Ⅲ angiotensin II Ⅲ reactive oxygen species Ⅲ hyperlipidemia Ⅲ hypertension C arbon monoxide (CO), a low-molecular-weight diatomic gaseous molecule, has been considered a dangerous inhalation hazard, because CO binds to hemoglobin with high affinity. 1 CO arises primarily from the large-scale environment and human activities, such as volcanic emissions, forest fires, plant metabolisms, industrial processes, and exhaust emissions.However, recent studies have revealed that CO has profound effects on intracellular signaling processes. The physiological signaling effects of CO involve modulation of soluble guanylate cyclase and subsequent upregulation of cGMP production similar to those of NO. Additional mechanisms include the modulation of several mitogen-activated protein kinase activation pathways. 2,3 CO is endogenously produced during the processes of heme catabolism via heme oxygenase (HO). 4 Because protective roles of HO under various pathophysiological processes have been reported, 5-7 the roles of CO under these processes have currently drawn attention.The vasodilating properties of CO have been investigated in the cardiovascular system. 4,8 CO also has antiapoptotic 9 and anti-inflammatory 10 potentials. However...

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“…bolus) was administered 20 min prior to occlusion (n = 10); (5) ZnPP/TMP-10 group: with 2 h-pretreatment of a HO inhibitor zinc protoporphyrin (ZnPP; 50 lg per rat, i.p.) [16], TMP 10 mg/kg (i.v. bolus) was administered 20 min prior to occlusion (n = 6).…”

Section: Animal Preparationmentioning

confidence: 99%

Tetramethylpyrazine induces heme oxygenase-1 expression and attenuates myocardial ischemia/reperfusion injury in rats

et al. 2006

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The accumulation of oxygen free radicals and activation of neutrophils are strongly implicated as pathophysiological mechanisms mediating myocardial ischemia/reperfusion injury. Heme oxygenase-1 (HO-1) has been reported to play a protective role in oxidative tissue injuries. In this study, the cardioprotective activity of tetramethylpyrazine (TMP), an active ingredient of Chinese medicinal herb Ligusticum wallichii Franchat, was evaluated in an open-chest anesthetized rat model of myocardial ischemia/reperfusion injury. Pretreatment with TMP (5 and 10 mg/kg, i.v.) before left coronary artery occlusion significantly suppressed the occurrence of ventricular fibrillation. After 45 min of ischemia and 1 h of reperfusion, TMP (5 and 10 mg/kg) caused a significant reduction in infarct size and induced HO-1 expression in ischemic myocardium. The HO inhibitor ZnPP (50 lg/rat) markedly reversed the anti-infarct action of TMP.

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Carbon Monoxide Protects Against Cardiac Ischemia—Reperfusion Injury In Vivo via MAPK and Akt—eNOS Pathways

Cited by 138 publications

References 41 publications

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

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

Synergetic Antioxidant and Vasodilatory Action of Carbon Monoxide in Angiotensin II–Induced Cardiac Hypertrophy

Tetramethylpyrazine induces heme oxygenase-1 expression and attenuates myocardial ischemia/reperfusion injury in rats

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