Abstract
Aim:
To investigate which endothelin receptors mediated isoproterenol (ISO)-induced downregulation of FKBP12.6/12 in cardiomyocytes and study whether argirhein, a novel compound containing rhein and L-arginine that has anti-inflammatory activity, could reverse the downregulation of FKBP12.6/12 induced by ISO.
Methods:
Neonatal rat cardiomyocytes were incubated with ISO to downregulate FKBP12.6/12. Then the cells were treated with a selective ETA blocker (PD156707) and a ETB blocker (IRL1038), a dual ETA/ETB antagonist (CPU0213), and argirhein, respectively. FKBP12.6/12 expression was assayed by RT-PCR, Western blot, and immunocytochemistry.
Results:
The expression of FKBP12.6 mRNA was reduced by 37.7% (P<0.01) and 28.9% (P<0.05) relative to the control by ISO 1 and 0.1 μmol/L, respectively, but no response to ISO 0.01 μmol/L was observed in vitro. FKBP12.6/12 protein expression was reduced by 47.2% (P<0.01) and 37.8% (P<0.05) by ISO 1 and 0.1 μmol/L, respectively. This decrease was reversed significantly by PD156707, or IRL1038, and CPU0213. CPU0213 was more potent than either PD156707 or IRL-1038. Argirhein 10 μmol/L blunted the downregulation of FKBP12.6/12 by ISO, as demonstrated by the rising mRNA and protein levels and by the fluorescent density of the ISO-incubated cardiomyocytes.
Conclusion:
In cardiomyocytes, the ISO induced downregulation of FKBP12.6/12 is modulated by both ETA and ETB. A new compound, argirein, reversed the down-regulation of FKBP12.6/12 expression in myocardial cells stimulated with ISO.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (No 81070145) and the National Key New Drug Innovation Program, Ministry of Science and Technology of China, No 2009ZX09308.
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Zhang, Gl., Dai, Dz., Xi, T. et al. Isoproterenol-induced FKBP12.6/12 downregulation is modulated by ETA and ETB receptors and reversed by argirhein, a derivative of rhein. Acta Pharmacol Sin 32, 223–229 (2011). https://doi.org/10.1038/aps.2010.177
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DOI: https://doi.org/10.1038/aps.2010.177
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