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Increased myocardial contractility and enhanced exercise function in transgenic mice overexpressing either adenylyl cyclase 5 or 8

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Abstract

Objective

ß-adrenergic receptors (ßARs) are powerful regu- lators of cardiac function in vivo, activating heterotrimeric G proteins and the effector molecule adenylyl cyclase (AC). Interestingly, cardiac-specific overexpression of different AC isoforms leads to variable changes in cardiac function. Whether AC overexpression affects intrinsic cardiac contractility in an isoform-specific fashion determining a change in exercise capacity is currently unknown.

Methods

To address this issue, we performed load-independent measurements of cardiac systolic and diastolic function by pressure–volume (PV) loop analysis in intact wild-type mice (WT) and transgenic mice overexpressing the AC isoforms 5 or 8.

Results

Here we show that cardiac overexpression of either AC5 or AC8 transgenic mice determined an increase in intrinsic cardiac contractility. Interestingly, AC8 transgenic mice displayed a significantly greater increase in cardiac contractility and improved active phase of relaxation. Despite these differences detected by PV loop analysis, both AC5 and AC8 mice showed a marked increase in exercise capacity on treadmill testing.

Conclusions

Our results demonstrate that load-independent measurements of cardiac function are needed to compare different groups of genetically-modified mouse models and to detect subtle AC isoform-specific changes in cardiac performance.

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Acknowledgements

This work was supported, in part, by grant HL56687 (NIH) to Howard A. Rockman and by grant PRIN2005 by Ministero dellUniversità e della Ricerca Scientifica to Massimo Chiariello.

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Authors and Affiliations

  1. Division of Cardiology, University Federico II of Naples, Via Pansini 5, 80131, Naples, Italy

    Giovanni Esposito MD, PhD, Cinzia Perrino MD, PhD, Maria Piera Petretta MD, Maria Carmen De Angelis MD & Massimo Chiariello MD

  2. Drug Safety Research Labs, Astellas Pharma Inc, Osaka, Japan

    Tohru Ozaki PhD

  3. Kobe Redcross Hospital, Kobe, Japan

    Hideyuki Takaoka MD, PhD

  4. NSERM U-99, Hôpital Henri Mondor, Créteil, France

    Nicole Defer PhD & Jacques Hanoune MD, PhD

  5. Dept. of Medicine and Cell Biology, Duke University Medical Center, Durham, NC, USA

    Lan Mao MD & Howard A. Rockman MD

Authors
  1. Giovanni Esposito MD, PhD
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  2. Cinzia Perrino MD, PhD
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  3. Tohru Ozaki PhD
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  4. Hideyuki Takaoka MD, PhD
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  8. Lan Mao MD
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  9. Jacques Hanoune MD, PhD
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  10. Howard A. Rockman MD
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  11. Massimo Chiariello MD
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Corresponding author

Correspondence to Giovanni Esposito MD, PhD.

Additional information

Returned for 1. revision: 2 January 2007 1. Revision received: 16 August 2007

Returned for 2. revision: 24 September 2007 2. Revision received: 2 October 2007

Giovanni Esposito and Cinzia Perrino equally contributed to this work.

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Esposito, G., Perrino, C., Ozaki, T. et al. Increased myocardial contractility and enhanced exercise function in transgenic mice overexpressing either adenylyl cyclase 5 or 8. Basic Res Cardiol 103, 22–30 (2008). https://doi.org/10.1007/s00395-007-0688-6

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  • DOI: https://doi.org/10.1007/s00395-007-0688-6

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