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

Gene Therapy volume 13, pages 8–19 (2006)Cite this article

Abstract

The serine-threonine kinase Akt/PKB mediates stimuli from different classes of cardiomyocyte receptors, including the growth hormone/insulin like growth factor and the β-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 (Ca2+) handling, oxygen consumption, and β-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 Ca2+ handling were evaluated in an isolated isovolumic buffer-perfused, aequorin-loaded whole heart preparations 10 days after the surgery. The Ca2+–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 2.6±0.2 versus 2.7±0.1 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 Ca2+ available to the contractile machinery (+19% versus controls) and by enhanced myofilament Ca2+ responsiveness, documented by an increased maximal Ca2+-activated pressure (+19% versus controls) and a shift to the left of the Ca2+–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% (P<0.01). Phospholamban, calsequestrin, and ryanodine receptor LV mRNA and protein content were not different among the study groups, while sarcoplasmic reticulum Ca2+ ATPase protein levels were significantly increased in Ad.Akt rats. β-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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Acknowledgements

This work was supported in part by grants from the Italian National Institute of Health, The Italian Ministy of Education (MIUR), and Adriano Buzzati-Traverso Foundation.

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Authors and Affiliations

  1. Department of Clinical Medicine and Cardiovascular Sciences, University ‘Federico II’, Naples, Italy

    A Cittadini, M G Monti, G Iaccarino, F Di Rella, A Di Gianni, D Sorriento, B Trimarco & L Saccà

  2. Molecular Oncology Research Institute, Tufts, New England Medical Center, Boston, MA, USA

    P N Tsichlis

  3. Medizinische Universitätsklinik, Würzburg, Germany

    H Strömer

  4. Instituto Superiore Sanita', Rome, Italy

    C Peschle

  5. San Raffaele Biomedical Science Park, Rome-Multimedica Hospital, Milan, Italy

    G Condorelli

  6. Institute of Molecular Medicine, University of California, San Diego, CA, USA

    G Condorelli

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  1. A Cittadini
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Correspondence to A Cittadini.

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Presented in part at the Annual La Jolla-Kyoto-Horizons on heart failure, La Jolla, CA, December 16–19, 2002.

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Cittadini, A., Monti, M., Iaccarino, G. et al. Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling. Gene Ther 13, 8–19 (2006). https://doi.org/10.1038/sj.gt.3302589

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