Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letters to the Editor
  • Published:

Calcineurin inhibitors and cardiac hypertrophy

Nature Medicine volume 4, pages 1092–1093 (1998)Cite this article

Many studies indicate that myocyte hypertrophy is associated with the elevation of or enhanced sensitivity to intracellular calcium1. Calcineurin is a calcium-dependent phosphatase that activates the NF-AT transcription factors2. Recently, it was reported that transgenic mice expressing activated forms of calcineurin or NF-AT3 in the heart develop cardiac hypertrophy and heart failure with similarities to the human disease3. Hypertrophy in transgenic mice expressing activated calcineurin was blocked by administration of the immunosuppressant cyclosporin A (CyA), an inhibitor of calcineurin activity2. These data have led to speculation that pharmacological inhibition of the calcineurin pathway may be useful in the treatment of cardiac hypertrophy. To examine the role of calcineurin in hemodynamic load-induced hypertrophy, we tested whether calcineurin inhibitors affect hypertrophy in rats with constricted abdominal aortas.

The abdominal aortas above the renal arteries of male Sprague-Dawley rats (400–450g) were constricted for 14 days before they were killed4. Heart weight and total body weight were measured on the day the rats were killed. The heart weight/body weight ratio increased 43% in the constricted rats compared with that in sham-operated rats ( Table). CyA (20 mg/kg) was administered by subcutaneous injection immediately after constriction, and it was also included in the drinking water (20 mg/kg per day) for 14 days (Group III). Alternatively, CyA (40 mg/kg) was administered 3 days before aortic constriction, followed by 17 days of CyA administered in the drinking water at 40 mg/kg per day (Group IV). At 7 days after surgery, the circulating level of CyA in blood was 417 ± 137 μg/L with the low dose, and 924 ± 172 μg/L with the high dose; these are comparable to therapeutic levels observed in clinical trials5. Blood hemoglobin decreased by 20% (P < 0.01), and hematocrit decreased by 18% (P < 0.01) at the low CyA dose, indicating drug action. Treatment with CyA at the high dose decreased hemoglobin by 23% ( P < 0.01) and hematocrit by 22% (P < 0.01). However, treatment of rats with constricted aortas with CyA at either dose, high or low, had no effect on their heart weight/body weight ratio compared with that in rats with constricted aortas receiving no drug therapy (Table). Administration of FK506 (2mg/kg by intravenous injection), another immune-suppressive agent that targets calcineurin, also had no affect on pressure overload hypertrophy in this model (Group V). A higher dose of FK506 (4 mg/kg by intravenous injection 3 days before surgery and at the time of surgery) led to a 90% mortality rate (Group VI; Table). Analysis of the surviving rat in Group VI did not indicate a reduction in hypertrophy. It has been reported that CyA treatment can induce left ventricular hypertrophy in transplant patients6 and increase heart weight in animals that undergo heart transplantation7. However, in the absence of aortic constriction, administration of CyA (Group VII) or FK506 (Group VIII) to rats had no effect on their heart weight/body weight ratio (Table).

Table 1 Effect of calcineurin inhibitors on pressure overload-induced cardiac hypertrophy
Full size table

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Schwartz, K. & Mercadier, J.J. Molecular and cellular biology of heart failure. Curr. Opin. Cardiol. 11, 227–236 (1996).

    Article  CAS  Google Scholar 

  2. Rao, A., Luo, C. & Hogan, P.G. Transcription factors of the NFAT family: regulation and function. Annu. Rev. Immunol. 15, 707– 747 (1997).

    Article  CAS  Google Scholar 

  3. Molkentin, J.D. et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93, 215– 228 (1998).

    Article  CAS  Google Scholar 

  4. Hasegawa, K., Lee, S.J., Jobe, S.M., Markham, B.E. & Kitsis, R.N. cis-acting sequences that mediate induction of ß-myosin heavy chain gene expression during left ventricular hypertrophy due to aortic constriction. Circulation 96, 3943–3953 (1997).

    Article  CAS  Google Scholar 

  5. Radermacher, J. et al. Pronounced renal vasoconstriction and systemic hypertension in renal transplant patients treated with cyclosporin A versus FK 506. Transpl. Int. 11, 3–10 ( 1998).

    Article  CAS  Google Scholar 

  6. McKoy, R.C. et al. Left ventricular hypertrophy in cyclosporine-induced systemic hypertension after cardiac transplantation. Am. J. Cardiol. 62, 1140–1142 (1988).

    Article  CAS  Google Scholar 

  7. Sadeghi, A.M. et al. Cyclosporine increases rat heart weight in heterotopic transplants. Curr. Surg. 44, 51–52 (1987).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cardiovascular Research St. Elizabeth's Medical Center and Tufts University School of Medicine, 736 Cambridge Street, Boston, 02135, MA, USA

    Zhengyu Luo, Kuo-Gi Shyu & Kenneth Walsh

  2. Department of Physiology Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland , 44106, OH, USA

    Antonio Gualberto

Authors
  1. Zhengyu Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kuo-Gi Shyu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antonio Gualberto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenneth Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenneth Walsh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Luo, Z., Shyu, KG., Gualberto, A. et al. Calcineurin inhibitors and cardiac hypertrophy. Nat Med 4, 1092–1093 (1998). https://doi.org/10.1038/2578

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/2578

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing