Hypertrophic cardiomyopathy associated with tacrolimus in paediatric transplant patients

Atkison, Paul; Joubert, Gary; Barron, Antony; Grant, David; Wall, William; Rosenberg, Hans; Howard, J; Williams, Sylvain; Stiller, C. R.; Paradis, Khazal; Seidman, E. G.

doi:10.1016/s0140-6736(95)90011-x

Cited by 185 publications

(103 citation statements)

References 6 publications

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“…In support of the former is the observation that administration of FK-506 (tacrolimus), an immunosuppressant that binds to FKBP12.6, has been associated with the development of hypertrophic cardiomyopathy in children. 31,32 FKBP12.6 itself is known to bind to and modulate channel gating of the Ryr2 receptor. 33,34 Knockout mice lacking either FKBP12 or Ryr2 die during embryogenesis, 35,36 principally because of disruption of heart tube development.…”

Section: Discussionmentioning

confidence: 99%

Right Ventricular Hypertrophy Secondary to Pulmonary Hypertension Is Linked to Rat Chromosome 17

et al. 2001

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Background-Fischer 344 (F344) rats are relatively resistant to hypoxia-induced right ventricular (RV) hypertrophy compared with the Wistar-Kyoto (WKY) strain. These 2 strains were used to examine the genetic basis for the differential response. Methods and Results-Male F 2 offspring from an F344ϫWKY intercross were exposed to hypoxia (10% O 2 ) for 3 weeks, and pulmonary artery pressure and cardiac chamber weights were measured. Genomic DNA was screened by use of polymorphic microsatellite markers across the whole genome (excluding the sex chromosomes). A quantitative trait locus (QTL) for RV weight was identified on rat chromosome 17 (lod score 6.5) that accounted for 22% of the total variance of RV weight in the F 2 population and was independent of pulmonary artery pressure. The peak was centered over marker D17Rat41, close to Chrm3, with a 1-lod support interval of 5 cM. Comparison of homologous regions in mice and humans suggested that Ryr2, the cardiac isoform of the ryanodine receptor, colocalizes with our QTL. A panel of somatic cell hybrids and fluorescence in situ hybridization mapped Ryr2 close to the gene Chrm3 within our QTL.

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Section: Discussionmentioning

confidence: 99%

Right Ventricular Hypertrophy Secondary to Pulmonary Hypertension Is Linked to Rat Chromosome 17

et al. 2001

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“…Binding of each of these drug-protein complexes to a catalytic subunit of carcineurin causes inhibition of signal transduction in T cell activation [3]. However, these agents have some adverse side-effects such as nephrotoxicity and chronic rejection [4,5]. Another potent immunosuppressive agent is desired to develop a safer medical treatment.…”

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confidence: 99%

Ushikulides A and B, Immunosuppressants Produced by a Strain of Streptomyces sp.

2005

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Novel immunosuppressants, ushikulides A and B, were isolated from the culture broth of Streptomyces sp. IUK-102. Ushikulides A and B both have the same molecular formula, determined as C 40 H 68 O 10 . The structures of both compounds were elucidated to be novel 22-membered macrolides. Both compounds showed immunosuppressive activity for murine splenocyte proliferation in vitro. Binding of each of these drug-protein complexes to a catalytic subunit of carcineurin causes inhibition of signal transduction in T cell activation [3]. However, these agents have some adverse side-effects such as nephrotoxicity and chronic rejection [4,5]. Another potent immunosuppressive agent is desired to develop a safer medical treatment. During our screening for immunosuppressants from microbial products, novel immunosuppressants ushikulides A (1) and B (2) were found in the culture broth of Streptomyces sp. IUK-102 (Fig. 1). This paper describes the isolation, structure elucidation, and biological activities of these compounds.The producing strain, Streptomyces sp. IUK-102, was isolated from a soil sample collected in Ibaraki prefecture, J. Antibiot. 58 (6)

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“…Mice deficient in FKBP12 show severe heart defects associated with loss of function of cardiac ryanodine receptors (14). Similarly, treatment with high doses of FK506 can lead to severe heart failure (15).…”

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confidence: 99%

Rapamycin Blocks Sexual Development in Fission Yeast through Inhibition of the Cellular Function of an FKBP12 Homolog

Weisman

Finkelstein

Choder

2001

Journal of Biological Chemistry

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FKBP12 is a ubiquitous and a highly conserved prolyl isomerase that binds the immunosuppressive drugs FK506 and rapamycin. Members of the FKBP12 family have been implicated in many processes that include intracellular protein folding, transport, and assembly. In the budding yeast Saccharomyces cerevisiae and in human T cells, rapamycin forms a complex with FKBP12 that inhibits cell cycle progression by inhibition of the TOR kinases. We reported previously that rapamycin does not inhibit the vegetative growth of the fission yeast Schizosaccharomyces pombe; however, it specifically inhibits its sexual development. Here we show that disruption of the S. pombe FKBP12 homolog, fkh1 ؉ , at its chromosomal locus results in a mating-deficient phenotype that is highly similar to that obtained by treatment of wild type cells with rapamycin. A screen for fkh1 mutants that can confer rapamycin resistance identified five amino acids in Fkh1 that are critical for the effect of rapamycin in S. pombe. All five amino acids are located in the putative rapamycin binding pocket. Together, our findings indicate that Fkh1 has an important role in sexual development and serves as the target for rapamycin action in S. pombe.

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Hypertrophic cardiomyopathy associated with tacrolimus in paediatric transplant patients

Cited by 185 publications

References 6 publications

Right Ventricular Hypertrophy Secondary to Pulmonary Hypertension Is Linked to Rat Chromosome 17

Right Ventricular Hypertrophy Secondary to Pulmonary Hypertension Is Linked to Rat Chromosome 17

Ushikulides A and B, Immunosuppressants Produced by a Strain of Streptomyces sp.

Rapamycin Blocks Sexual Development in Fission Yeast through Inhibition of the Cellular Function of an FKBP12 Homolog

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