Akt Promotes Survival of Cardiomyocytes In Vitro and Protects Against Ischemia-Reperfusion Injury in Mouse Heart

Fujio, Yasushi; Nguyen, Thao; Wencker, Detlef; Kitsis, Richard N.; Walsh, Kenneth

doi:10.1161/01.cir.101.6.660

Cited by 760 publications

(574 citation statements)

References 31 publications

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“…The PI3K/Akt cascade is an important survival pathway in the heart. Akt overexpression leads to increased survival and improved myocardial function following I/R injury [21][22][23][24] in a manner similar to HO-1. Recent evidence suggests that these two enzyme systems interact both at the posttranscriptional and post-translational levels [25,26], and may function in a co-dependent function to confer cytoprotection [25].…”

Section: Introductionmentioning

confidence: 90%

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: Introductionmentioning

confidence: 90%

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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“…Myocardial apoptosis was qualitatively analyzed by TUNEL staining in the remote zone as previously described [26]. Myocyte identity was indicated by staining with anti-α-sarcomeric actin antibody (Sigma) [27]. Myocardial interstitial fibrosis was assessed by MT staining in the remote zone as previously described [28].…”

Section: Histologymentioning

confidence: 99%

Adiponectin protects against the development of systolic dysfunction following myocardial infarction

Shibata

Izumiya

Sato

et al. 2007

Journal of Molecular and Cellular Cardiology

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“…The principal and most extensively investigated physiological actions of Akt consist of growth activation and apoptosis inhibition, both consistently documented in many systems. [4][5][6][7][8][9] However, it appears that Akt may also be involved in the regulation of myocardial contractility. A recently generated transgenic mouse with cardiac-restricted overexpression of constitutively active Akt, the E40K, exhibited a phenotype characterized not only by cardiomyocyte hypertrophy but also by a remarkable increase of myocardial contractility.…”

Section: Introductionmentioning

confidence: 99%

Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling

et al. 2005

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The serine-threonine kinase Akt/PKB mediates stimuli from different classes of cardiomyocyte receptors, including the growth hormone/insulin like growth factor and the b-adrenergic receptors. Whereas the growth-promoting and antiapoptotic properties of Akt activation are well established, little is known about the effects of Akt on myocardial contractility, intracellular calcium (Ca 2+ ) handling, oxygen consumption, and b-adrenergic pathway. To this aim, Sprague-Dawley rats were subjected to a wild-type Akt in vivo adenoviral gene transfer using a catheter-based technique combined with aortopulmonary crossclamping. Left ventricular (LV) contractility and intracellular Ca 2+ handling were evaluated in an isolated isovolumic bufferperfused, aequorin-loaded whole heart preparations 10 days after the surgery. The Ca 2+ -force relationship was obtained under steady-state conditions in tetanized muscles. No significant hypertrophy was detected in adenovirus with wild-type Akt (Ad.Akt) versus controls rats (LV-to-body weight ratio 2.670.2 versus 2.770.1 mg/g, controls versus Ad.Akt, P, NS). LV contractility, measured as developed pressure, increased by 41% in Ad.Akt. This was accounted for by both more systolic Ca 2+ available to the contractile machinery (+19% versus controls) and by enhanced myofilament Ca 2+ responsiveness, documented by an increased maximal Ca 2+ -activated pressure (+19% versus controls) and a shift to the left of the Ca 2+ -force relationship. Such increased contractility was paralleled by a slight increase of myocardial oxygen consumption (14%), while titrated dose of dobutamine providing similar inotropic effect augmented oxygen consumption by 39% (Po0.01). Phospholamban, calsequestrin, and ryanodine receptor LV mRNA and protein content were not different among the study groups, while sarcoplasmic reticulum Ca 2+ ATPase protein levels were significantly increased in Ad.Akt rats. b-Adrenergic receptor density, affinity, kinase-1 levels, and adenylyl cyclase activity were similar in the three animal groups. In conclusion, our results support an important role for Akt/PKB in the regulation of myocardial contractility and mechanoenergetics.

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Akt Promotes Survival of Cardiomyocytes In Vitro and Protects Against Ischemia-Reperfusion Injury in Mouse Heart

Abstract: Background-IGF-1 has been shown to protect myocardium against death in animal models of infarct and ischemia-reperfusion injury. In the present study, we investigated the role of the IGF-1-regulated protein kinase Akt in cardiac myocyte survival in vitro and in vivo.

Cited by 760 publications

References 31 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

Adiponectin protects against the development of systolic dysfunction following myocardial infarction

Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling

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