Adrenomedullin Infusion Attenuates Myocardial Ischemia/Reperfusion Injury Through the Phosphatidylinositol 3-Kinase/Akt-Dependent Pathway

Okumura, Hiroyuki; Nagaya, Noritoshi; Itoh, Takefumi; Okano, Ichiro; Hino, Jun; Mori, Kenji; Tsukamoto, Yoshitane; Ishibashi‐Ueda, Hatsue; Miwa, Soichi; Tambara, Keiichi; Toyokuni, Shinya; Yutani, Chikao; Kangawa, Kenji

doi:10.1161/01.cir.0000109214.30211.7c

Cited by 153 publications

(102 citation statements)

References 34 publications

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“…Additionally, although total PI3K blockade might be detrimental to tissue survival, the same is not necessarily true for isoform-specific intervention. For example, wortmannin eliminates the cardioprotective effects of numerous agents including insulin (29), IGF1 (30), erythropoietin (31), adrenomedullin (32), and opioids (33), as well as both ischemic pre-and postconditioning (23,34), demonstrating the potential for at least some PI3K isoforms to ameliorate ischemic tissue damage. Transgenic mice overexpressing a kinase-inactive PI3K␥ in their cardiomyocytes, however, develop equivalent sized infarcts, as do wild-type mice (24), suggesting this isoform at least is not requisite for balancing cardiomyocyte survival.…”

Section: Discussionmentioning

confidence: 99%

Phosphoinositide 3-kinase γ/δ inhibition limits infarct size after myocardial ischemia/reperfusion injury

Doukas¹,

Wrasidlo²,

Noronha³

et al. 2006

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

118

102

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Although phosphoinositide 3-kinases (PI3Ks) play beneficial pro-cell survival roles during tissue ischemia, some isoforms (␥ and ␦) paradoxically contribute to the inflammation that damages these same tissues upon reperfusion. We therefore considered the possibility that selectively inhibiting proinflammatory PI3K isoforms during the reperfusion phase could ultimately limit overall tissue damage seen in ischemia/reperfusion injuries such as myocardial infarction. Panreactive and isoform-restricted PI3K inhibitors were identified by screening a novel chemical family; molecular modeling studies attributed isoform specificity based on rotational freedom of substituent groups. One compound (TG100-115) identified as a selective PI3K ␥/␦ inhibitor potently inhibited edema and inflammation in response to multiple mediators known to participate in myocardial infarction, including vascular endothelial growth factor and platelet-activating factor; by contrast, endothelial cell mitogenesis, a repair process important to tissue survival after ischemic damage, was not disrupted. In rigorous animal MI models, TG100-115 provided potent cardioprotection, reducing infarct development and preserving myocardial function. Importantly, this was achieved when dosing well after myocardial reperfusion (up to 3 h after), the same time period when patients are most accessible for therapeutic intervention. In conclusion, by targeting pathologic events occurring relatively late in myocardial damage, we have identified a potential means of addressing an elusive clinical goal: meaningful cardioprotection in the postreperfusion time period.edema ͉ inflammation ͉ myocardial infarct ͉ VEGF

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Section: Discussionmentioning

confidence: 99%

Phosphoinositide 3-kinase γ/δ inhibition limits infarct size after myocardial ischemia/reperfusion injury

Doukas¹,

Wrasidlo²,

Noronha³

et al. 2006

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

118

102

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“…Adult male Sprague-Dawley rats were anesthetised, ventilated using room air through a tracheotomy, and exposed to thoracotomy crossing the fifth intercostal space [15]. At least six rats were used in each group.…”

Section: In Vivo Ischemia/reperfusionmentioning

confidence: 99%

Retracted: Cardiac release of urocortin precedes the occurrence of irreversible myocardial damage in the rat heart exposed to ischemia/reperfusion injury

Knight¹,

Chen‐Scarabelli²,

Yuan³

et al. 2008

FEBS Letters

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This study evaluates whether cardiac ischemia induces release of urocortin, before and independently from myocyte cell death. Urocortin levels rose after 5-min ischemia and peaked after 10-min ischemia, when cell death was not detected. However, myocyte apoptosis and/or necrosis occurred following 20-and 30-min ischemia, which paralleled a fall in urocortin levels, suggesting that urocortin expression and release are mainly sustained by metabolically challenged, though still viable myocytes. Hence, since cardiac release of urocortin, unlike that of conventional biomarkers, occurs before and apart from cell death, urocortin levels may be clinically useful in the diagnosis of sublethal myocardial ischemia.

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“…AM-induced vasodilatation and myocardial protection is mediated through the activation of the phosphatidylinositol 3-kinase (PI3K)͞Akt-dependent pathway (15,16). The phosphorylation of Akt in DRG is involved in the maintenance of inflammatory pain caused by intraplantar injection of capsaicin (17).…”

Section: Intrathecal Am-induced Pain Response Is Mediated Through Thementioning

confidence: 99%

A role for adrenomedullin as a pain-related peptide in the rat

Chabot

Quirion

2006

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

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Adrenomedullin Infusion Attenuates Myocardial Ischemia/Reperfusion Injury Through the Phosphatidylinositol 3-Kinase/Akt-Dependent Pathway

Cited by 153 publications

References 34 publications

Phosphoinositide 3-kinase γ/δ inhibition limits infarct size after myocardial ischemia/reperfusion injury

Phosphoinositide 3-kinase γ/δ inhibition limits infarct size after myocardial ischemia/reperfusion injury

Retracted: Cardiac release of urocortin precedes the occurrence of irreversible myocardial damage in the rat heart exposed to ischemia/reperfusion injury

A role for adrenomedullin as a pain-related peptide in the rat

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