Calcineurin inhibitors and cardiac hypertrophy (original) (raw)

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

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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

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  1. Zhengyu Luo
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  2. Kuo-Gi Shyu
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  3. Antonio Gualberto
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  4. Kenneth Walsh
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Correspondence toKenneth Walsh.

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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

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