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Prevention of RhoA activation and cofilin-mediated actin polymerization mediates the antihypertrophic effect of adenosine receptor agonists in angiotensin II- and endothelin-1-treated cardiomyocytes

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Abstract

Adenosine receptor activation has been shown to be associated with diminution of cardiac hypertrophy and it has been suggested that endogenously produced adenosine may serve to blunt pro-hypertrophic processes. In the present study, we determined the effects of two pro-hypertrophic stimuli, angiotensin II (Ang II, 100 nM) and endothelin-1 (ET-1, 10 nM) on Ras homolog gene family, member A (RhoA)/Rho-associated, coiled-coil containing protein kinase (ROCK) activation in cultured neonatal rat ventricular myocytes and whether the latter serves as a target for the anti-hypertrophic effect of adenosine receptor activation. Both hypertrophic stimuli potently increased RhoA activity with peak activation occurring 15–30 min following agonist addition. These effects were associated with significantly increased phosphorylation (inactivation) of cofilin, a downstream mediator of RhoA, an increase in actin polymerization, and increased activation and nuclear import of p38 mitogen activated protein kinase. The ability of both Ang II and ET-1 to activate the RhoA pathway was completely prevented by the adenosine A1 receptor agonist N 6-cyclopentyladenosine, the A2a receptor agonist 2-p-(2-carboxyethyl)-phenethylamino-5′-N-ethylcarboxamidoadenosine, the A3 receptor agonist N 6-(3-iodobenzyl)adenosine-5′-methyluronamide as well as the nonspecific adenosine analog 2-chloro adenosine. All effects of specific receptor agonists were prevented by their respective receptor antagonists. Moreover, all adenosine agonists prevented either Ang II- or ET-1-induced hypertrophy, a property shared by the RhoA inhibitor Clostridium botulinum C3 exoenzyme, the ROCK inhibitor Y-27632 or the actin depolymerizing agent latrunculin B. Our study therefore demonstrates that both Ang II and ET-1 can activate the RhoA pathway and that prevention of the hypertrophic response to both agonists by adenosine receptor activation is mediated by prevention of RhoA stimulation and actin polymerization.

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Acknowledgments

This work was supported by a Grant from the Heart and Stroke Foundation of Ontario. Morris Karmazyn holds a Tier 1 Canada Research Chair in Experimental Cardiology.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada

    Asad Zeidan, Xiaohong Tracey Gan, Ashley Thomas & Morris Karmazyn

  2. Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon

    Asad Zeidan

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  1. Asad Zeidan
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  2. Xiaohong Tracey Gan
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  4. Morris Karmazyn
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Correspondence to Morris Karmazyn.

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Zeidan, A., Gan, X.T., Thomas, A. et al. Prevention of RhoA activation and cofilin-mediated actin polymerization mediates the antihypertrophic effect of adenosine receptor agonists in angiotensin II- and endothelin-1-treated cardiomyocytes. Mol Cell Biochem 385, 239–248 (2014). https://doi.org/10.1007/s11010-013-1832-2

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  • DOI: https://doi.org/10.1007/s11010-013-1832-2

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