Glimepiride induces nitric oxide production in human coronary artery endothelial cells via a PI3-kinase-Akt dependent pathway

Ueba, Hiroto; Kuroki, Masahide; Hashimoto, Shingo; Umemoto, Takuya; Yasu, Takanori; Ishikawa, San‐e; Saito, Muneyasu; Kawakami, Masanobu

doi:10.1016/j.atherosclerosis.2005.01.055

Cited by 38 publications

(27 citation statements)

References 15 publications

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“…Therefore, postconditioning mimetic action is not a class effect of sulfonylurea drugs. A previous study has shown that glimepiride induces Akt phosphorylation in human coronary artery endothelial cells (12). Here we also provide evidence that glimepiride induces phosphorylation of Akt in myocardium.…”

Section: Discussionsupporting

confidence: 82%

“…Phosphatidylinositol 3-kinase (PI3K) is a component of the RISK pathway and pharmacological activation of this kinase at reperfusion can mimic postconditioning (11). Interestingly, it has been reported that glimepiride activates PI3K in human coronary artery endothelial cells (12). Accordingly, an attractive hypothesis is that glimepiride activates PI3K in cardiac cells and treatment with glimepiride upon reperfusion can mimic the protection conferred by postconditioning.…”

Section: Introductionmentioning

confidence: 99%

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Glimepiride Treatment Upon Reperfusion Limits Infarct Size via the Phosphatidylinositol 3-Kinase/Akt Pathway in Rabbit Hearts

Nishida¹,

Sato²,

Nomura³

et al. 2009

J Pharmacol Sci

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Abstract. The phenomenon termed postconditioning, that is, brief episodes of ischemia / reperfusion at the onset of reperfusion reduce infarct size, is thought to involve the activation of the phosphatidylinositol 3-kinase (PI3K)/ Akt pathway. Treatment with a drug activating PI3K at the onset of reperfusion may confer a similar cardioprotection. The sulfonylurea glimepiride has been shown to activate PI3K in human endothelial cells. We therefore tested in rabbit hearts whether glimepiride can produce postconditioning-mimetic actions. Langendorff-perfused rabbit hearts were subjected to 30 min of global ischemia and 120 min of reperfusion, and infarct size was determined by triphenyltetrazolium staining. Phosphorylation of Akt was analyzed by Western blotting. Glimepiride (10 μM) treatment for the first 10 min of reperfusion significantly reduced infarct size from 67.2 ± 1.3% in controls to 35.8 ± 4.5% (P<0.01). This infarct size-limiting effect of glimepiride was abolished by a selective inhibitor of PI3K (5 μM LY294002, 65.4 ± 3.4%). Phosphorylation of the PI3K substrate Akt was significantly increased in glimepiridetreated hearts when compared to controls (P<0.05). Glimepiride-induced Akt phosphorylation was inhibited by LY294002. In conclusion, our study demonstrates that glimepiride treatment upon reperfusion reduces infarct size in rabbit hearts via a PI3K / Akt-mediated pathway. The postconditioning-mimetic action of glimepiride may be beneficial for the treatment of diabetic patients with ischemic heart disease.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Glimepiride Treatment Upon Reperfusion Limits Infarct Size via the Phosphatidylinositol 3-Kinase/Akt Pathway in Rabbit Hearts

Nishida¹,

Sato²,

Nomura³

et al. 2009

J Pharmacol Sci

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“…[50][51][52][53] It would be interesting to determine whether glimepiride facilitates IPC by activating the PI3K-Akt pathway in the diabetic heart. In this regard, glimepiride has been reported to activate Akt in both coronary endothelial cells, 43 human umbilical vein endothelial cells, 44 and adipocytes. 45 Furthermore, it has been reported that the peroxisome proliferator-activated receptor (PPAR)-g agonist, rosiglitazone, also has the ability to cardioprotect the diabetic rat heart through the activation of Akt.…”

Section: Discussionmentioning

confidence: 99%

Glimepiride Treatment Facilitates Ischemic Preconditioning in the Diabetic Heart

Hausenloy

Wynne

Mocanu

et al. 2012

J Cardiovasc Pharmacol Ther

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Aims: The diabetic heart is resistant to the myocardial infarct-limiting effects of ischemic preconditioning (IPC). This may be in part due to the downregulation of the phosphatidylinositol 3 0 -kinase-Akt pathway, an essential component of IPC protection. We hypothesized that treating the diabetic heart with the sulfonylurea, glimepiride, which has been reported to activate Akt, may lower the threshold required to protect the diabetic heart by IPC. Methods: Goto-Kakizaki rats (a type II lean model of diabetes) received glimepiride (20 mg/kg per d, by oral gavage) or vehicle for (a) 3 months (chronic treatment) or (b) 24 hours (subacute treatment). In the third group, glimepiride (10 mmol/L) was administered only to the isolated hearts on the Langendorff apparatus (acute treatment). All hearts were subjected to 35 minutes ischemia and 120 minutes reperfusion ex vivo, at the end of which infarct size was determined by tetrazolium staining. Preconditioning treatment comprised 1 (IPC-1) or 3 (IPC-3) cycles of 5 minutes global ischemia and 10 minutes reperfusion. Results: The diabetic heart was found to be resistant to IPC such that 3-IPC cycles, instead of the usual 1-IPC cycle, were required for cardioprotection. However, pretreatment with glimepiride lowered the threshold for IPC such that both 1 and 3 cycles of IPC elicited cardioprotection: chronic glimepiride treatment (IPC-1 31.9% + 3.8% and IPC-3 33.5% + 2.4% vs 43.9% + 1.4% control, P < .05; N > 6 per group); subacute glimepiride treatment (IPC-1 31.1% + 3.0% and IPC-3 29.3% + 3.3% vs 42.2% + 2.3% control, P < .05 N > 6 per group); and acute glimepiride treatment (IPC-1 28.2% + 3.7% and IPC-3 24.6% + 5.4% vs 41.9% + 5.4% control, P < .05; N > 6 per group). This effect of glimepiride was independent of changes in blood glucose. Conclusions: We report for the first time that glimepiride treatment facilitates the cardioprotective effect elicited by IPC in the diabetic heart.

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“…Biotechnology); anti-STAT3 (Upstate Biotechnology). Cardiomyocytes were treated with HBSP, EPO, or vehicle, and then cell lysates were prepared as previously described (41). Cell lysates were subjected to SDS/PAGE, and transferred to nitrocellulose membranes (Amersham Biosciences).…”

Section: Methodsmentioning

confidence: 99%

Cardioprotection by a nonerythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin

Ueba

Brines²,

Yamin³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Erythropoietin (EPO), originally identified for its critical hormonal role in regulating production and survival of erythrocytes, is a member of the type 1 cytokine superfamily. Recent studies have shown that EPO has cytoprotective effects in a wide variety of tissues, including the heart, by preventing apoptosis. However, EPO also has undesirable effects, such as thrombogenesis. In the present study, we investigated whether a helix B-surface peptide (HBSP), a nonerythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin, protects cardiomyocytes from apoptosis in vitro and in vivo. In cultured neonatal rat cardiomyocytes, HBSP clearly inhibited apoptosis (≈80%) induced by TNF-α, which was comparable with the effect of EPO, and activated critical signaling pathways of cell survival, including Akt, ERK1/2, and STAT3. Among these pathways, Akt was shown to play an essential role in HBSP-induced prevention of apoptosis, as assessed by using a small interfering RNA approach. In the dilated cardiomyopathic hamster (J2N-k), whose cardiac tissues diffusely expressed TNF-α, HBSP also inhibited apoptosis (≈70%) and activated Akt in cardiomyocytes. Furthermore, the levels of serum creatine kinase activity and of cardiac expression of atrial natriuretic peptide, a marker of chronic heart failure, were down-regulated in animals treated with HBSP. These data demonstrate that HBSP protects cardiomyocytes from apoptosis and leads to a favorable outcome in failing hearts through an Akt-dependent pathway. Because HBSP does not have the undesirable effects of EPO, it could be a promising alternative for EPO to treat cardiovascular diseases, such as myocardial infarction and heart failure.

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Glimepiride induces nitric oxide production in human coronary artery endothelial cells via a PI3-kinase-Akt dependent pathway

Cited by 38 publications

References 15 publications

Glimepiride Treatment Upon Reperfusion Limits Infarct Size via the Phosphatidylinositol 3-Kinase/Akt Pathway in Rabbit Hearts

Glimepiride Treatment Upon Reperfusion Limits Infarct Size via the Phosphatidylinositol 3-Kinase/Akt Pathway in Rabbit Hearts

Glimepiride Treatment Facilitates Ischemic Preconditioning in the Diabetic Heart

Cardioprotection by a nonerythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin

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