DOI: 10.1073/pnas.031371998. Targeted inhibition of calcineurin attenuates cardiac hypertrophy <i>in vivo</i>

Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo

10.1073/pnas.031371998

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

The Ca 2+ -calmodulin-activated Ser/Thr protein phosphatase calcineurin and the downstream transcriptional effectors of calcineurin, nuclear factor of activated T cells, have been implicated in the hypertrophic response of the myocardium. Recently, the calcineurin inhibitory agents cyclosporine A and FK506 have been extensively used to evaluate the importance of this signaling pathway in rodent models of cardiac hypertrophy. However, pharmacologic approaches have rendered equivocal results necessitating more specific or genetic-based inhibitory strategies. In this regard, we have generated Tg mice expressing the calcineurin inhibitory domains of Cain/Cabin-1 and A-kinase anchoring protein 79 specifically in the heart. ΔCain and ΔA-kinase-anchoring protein Tg mice demonstrated reduced cardiac calcineurin activity and reduced hypertrophy in response to catecholamine infusion or pressure overload. In a second approach, adenoviral-mediated gene transfer of ΔCain was performed in the adult rat myocardium to evaluate the effectiveness of an acute intervention and any potential species dependency. ΔCain adenoviral gene transfer inhibited cardiac calcineurin activity and reduced hypertrophy in response to pressure overload without reducing aortic pressure. These results provide genetic evidence implicating calcineurin as an important mediator of the cardiac hypertrophic response in vivo .

Bibliography

De Windt, L. J., Lim, H. W., Bueno, O. F., Liang, Q., Delling, U., Braz, J. C., Glascock, B. J., Kimball, T. F., del Monte, F., Hajjar, R. J., & Molkentin, J. D. (2001). Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo. Proceedings of the National Academy of Sciences, 98(6), 3322â3327.

Authors 11

Leon J. De Windt (first)
Hae W. Lim (additional)
Orlando F. Bueno (additional)
Qiangrong Liang (additional)
Ulrike Delling (additional)
Julian C. Braz (additional)
Betty J. Glascock (additional)
Thomas F. Kimball (additional)
Federica del Monte (additional)
Roger J. Hajjar (additional)
Jeffery D. Molkentin (additional)

References 44 Referenced 174

Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:36 a.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 8:42 a.m.)
Indexed	1 month, 4 weeks ago (July 2, 2025, 3:07 p.m.)
Issued	24 years, 5 months ago (March 13, 2001)
Published	24 years, 5 months ago (March 13, 2001)
Published Online	24 years, 5 months ago (March 13, 2001)
Published Print	24 years, 5 months ago (March 13, 2001)

Funders 0

None

BibTeX

@article{De_Windt_2001, title={Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo}, volume={98}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.031371998}, DOI={10.1073/pnas.031371998}, number={6}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={De Windt, Leon J. and Lim, Hae W. and Bueno, Orlando F. and Liang, Qiangrong and Delling, Ulrike and Braz, Julian C. and Glascock, Betty J. and Kimball, Thomas F. and del Monte, Federica and Hajjar, Roger J. and Molkentin, Jeffery D.}, year={2001}, month=mar, pages={3322–3327} }

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  "abstract": "<jats:p>\n            The Ca\n            <jats:sup>2+</jats:sup>\n            -calmodulin-activated Ser/Thr\n protein phosphatase calcineurin and the downstream transcriptional\n effectors of calcineurin, nuclear factor of activated T cells, have\n been implicated in the hypertrophic response of the myocardium.\n Recently, the calcineurin inhibitory agents cyclosporine A and FK506\n have been extensively used to evaluate the importance of this signaling\n pathway in rodent models of cardiac hypertrophy. However, pharmacologic\n approaches have rendered equivocal results necessitating more specific\n or genetic-based inhibitory strategies. In this regard, we have\n generated Tg mice expressing the calcineurin inhibitory domains of\n Cain/Cabin-1 and A-kinase anchoring protein 79 specifically in the\n heart. \u0394Cain and \u0394A-kinase-anchoring protein Tg mice demonstrated\n reduced cardiac calcineurin activity and reduced hypertrophy in\n response to catecholamine infusion or pressure overload. In a second\n approach, adenoviral-mediated gene transfer of \u0394Cain was\n performed in the adult rat myocardium to evaluate the effectiveness of\n an acute intervention and any potential species dependency. \u0394Cain\n adenoviral gene transfer inhibited cardiac calcineurin activity and\n reduced hypertrophy in response to pressure overload without reducing\n aortic pressure. These results provide genetic evidence implicating\n calcineurin as an important mediator of the cardiac hypertrophic\n response\n            <jats:italic>in vivo</jats:italic>\n            .\n          </jats:p>",
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