DOI: 10.1126/science.281.5383.1690. Prevention of Cardiac Hypertrophy in Mice by Calcineurin Inhibition

Prevention of Cardiac Hypertrophy in Mice by Calcineurin Inhibition

10.1126/science.281.5383.1690

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

Abstract

Hypertrophic cardiomyopathy (HCM) is an inherited form of heart disease that affects 1 in 500 individuals. Here it is shown that calcineurin, a calcium-regulated phosphatase, plays a critical role in the pathogenesis of HCM. Administration of the calcineurin inhibitors cyclosporin and FK506 prevented disease in mice that were genetically predisposed to develop HCM as a result of aberrant expression of tropomodulin, myosin light chain–2, or fetal β-tropomyosin in the heart. Cyclosporin had a similar effect in a rat model of pressure-overload hypertrophy. These results suggest that calcineurin inhibitors merit investigation as potential therapeutics for certain forms of human heart disease.

Bibliography

Sussman, M. A., Lim, H. W., Gude, N., Taigen, T., Olson, E. N., Robbins, J., Colbert, M. C., Gualberto, A., Wieczorek, D. F., & Molkentin, J. D. (1998). Prevention of Cardiac Hypertrophy in Mice by Calcineurin Inhibition. Science, 281(5383), 1690â1693.

Authors 10

Mark A. Sussman (first)
Hae W. Lim (additional)
Natalie Gude (additional)
Tyler Taigen (additional)
Eric N. Olson (additional)
Jeffrey Robbins (additional)
Melissa C. Colbert (additional)
Antonio Gualberto (additional)
David F. Wieczorek (additional)
Jeffery D. Molkentin (additional)

References 37 Referenced 377

10.1161/01.CIR.92.4.785
Abraham W. T., Bristow M. R., ibid. 96, 2755 (1997). / ibid. by Abraham W. T. (1997)
10.1126/science.280.5364.750
10.1016/S0955-0674(96)80053-6
10.1093/hmg/4.suppl_1.1721
10.1016/S0140-6736(97)01282-8
10.1007/BF00794070
10.1016/S0092-8674(00)81573-1
10.1038/386855a0
10.1126/science.279.5348.227
10.1161/01.RES.82.1.94
10.1172/JCI1167
TOT mice develop signs of cardiomyopathy by 11 to 12 days after birth. CsA (15 mg/kg of body weight twice a day) or FK506 (3 mg/kg twice a day) treatment was begun 9 days after birth and continued until day 24. Injections were administered subcutaneously. By day 24 vehicle-treated TOT mice showed a prominent dilated heart phenotype whereas CsA- and FK506-treated TOT mice did not develop a pathologic phenotype. Nontransgenic mice were treated with CsA over this same period to control for effects on normal developmental cardiac hypertrophy. At least five genetically identical mice were tested within each group. For morphometric measurements see Science Online (www.sciencemag.org).
Cryosections of hearts from TOT mice and nontransgenic mice were prepared for α-actinin and tropomodulin immunohistochemistry (6). The sections were generated from hearts subjected to the treatment regimens described in (7).
H. W. Lim and J. D. Molkentin data not shown.
10.1111/j.1749-6632.1993.tb17137.x
10.1016/S0021-9258(18)47212-2
; H. Husi M. A. Luyten M. G. Zurini ibid. p. 14199.
Calcineurin phosphatase activity was assayed with a [ 32 P]adenosine triphosphate–labeled phosphopeptide in the presence or absence of a specific calcineurin autoinhibitory peptide. The conditions of the assay were as described [
10.1074/jbc.273.12.7088
10.1007/s001090050182
J. G. Fewell et al. unpublished data.
The MLC2v transgenic mice gradually present with a hypertrophic phenotype by 8 weeks of age. These mice were split into two groups and treated with vehicle or CsA (15 mg/kg twice a day) beginning at 2 weeks after birth and continuing through 8 weeks. Nontransgenic littermate mice were analyzed in parallel to show normal heart morphology. For heart/body weight ratio measurements see Science Online (www.sciencemag.org).
M. Muthuchamy G. P. Boivin I. L. Grupp D. F. Wieczorek J. Mol. Cell. Cardiol. in press; M. Muthuchamy et al. J. Biol. Chem. 270 30593 (1995); (10.1074/jbc.270.51.30593)
Palmiter K. A., Kitada Y., Muthuchamy M., Wieczorek D. F., Solaro R. J., ibid. 271, 11611 (1996). / ibid. by Palmiter K. A. (1996)
Overexpression of the β-tropomyosin fetal isoform in transgenic mouse hearts results in dilated cardiomyopathy by 10 days after birth. Transgenic and nontransgenic mice are phenotypically indistinguishable at 3 days after birth. The two groups were treated with CsA (15 mg/kg twice a day) beginning on day 2 after birth and continuing through day 10 at which time the untreated transgenics began to die from severe cardiac dilation.
10.1172/JCI119727
Transgenic mice expressing an activated RAR in the heart show phenotypic signs of hypertrophy by 8 weeks of age. CsA was administered as in (14).
10.1113/expphysiol.1991.sp003560
10.1152/ajpcell.1995.269.3.C690
10.1146/annurev.immunol.15.1.707
James J., Robbins J., Am. J. Physiol. 273, H2105 (1997). / Am. J. Physiol. by James J. (1997)
Maier L. S., Brandes R., Pieske B., Bers D. M., ibid. 274, H1361 (1998). / ibid. by Maier L. S. (1998)
Six female Sprague-Dawley rats (200 to 225 g) were used for each treatment group. CsA (20 mg/kg once a day by intraperitoneal injection) was begun 2 days before surgical banding of the abdominal aorta above the renal arteries or sham operation. Treatment was maintained for six additional days at which time the experiment was terminated because of lethality in the banded CsA-treated group of rats. Lethality was presumably attributable to the lack of an adequate hypertrophic response that normally compensates for reduced blood flow below the level of an aortic constriction.
10.1097/00001573-199707000-00005
Haverich A., Costard-Jackle A., Cremer J., Herrmann G., Simon R., Transplant Proc. 26, 2713 (1994). / Transplant Proc. by Haverich A. (1994)
We thank S. Witt and T. Kimball for assistance with echocardiography. Supported by American Heart Association Scientist Development Grant 9730035N (J.D.M.) NIH grant HL58224-01 (M.A.S.) and funds from the Children's Hospital Research Foundation.

Dates

Type	When
Created	23 years, 1 month ago (July 27, 2002, 5:37 a.m.)
Deposited	1 year, 7 months ago (Jan. 12, 2024, 10:29 p.m.)
Indexed	2 weeks, 4 days ago (Aug. 20, 2025, 8:39 a.m.)
Issued	26 years, 11 months ago (Sept. 11, 1998)
Published	26 years, 11 months ago (Sept. 11, 1998)
Published Print	26 years, 11 months ago (Sept. 11, 1998)

Funders 0

None

BibTeX

@article{Sussman_1998, title={Prevention of Cardiac Hypertrophy in Mice by Calcineurin Inhibition}, volume={281}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.281.5383.1690}, DOI={10.1126/science.281.5383.1690}, number={5383}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Sussman, Mark A. and Lim, Hae W. and Gude, Natalie and Taigen, Tyler and Olson, Eric N. and Robbins, Jeffrey and Colbert, Melissa C. and Gualberto, Antonio and Wieczorek, David F. and Molkentin, Jeffery D.}, year={1998}, month=sep, pages={1690–1693} }

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