Improvement in cardiac function of diabetic rats by bosentan is not associated with changes in the activation of PKC isoforms |
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Authors: | Jihong Jiang Violet Yuen Hong Xiang John H McNeill PhD FRSC |
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Institution: | (1) Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, British Columbia, V6T 1Z3, Canada |
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Abstract: | We previously demonstrated that chronic treatment with the mixed endothelin A and B (ETA and ETB) receptor blocker bosentan improved isolated working heart function in streptozotocin (STZ) diabetic rats. Endothelin-1 (ET-1)
peptide levels, ET-1 mRNA and ETA and ETB receptor mRNA were all increased in diabetic hearts, but were unaffected by bosentan treatment, indicating that the beneficial
effects of bosentan on heart appear to be on downstream effectors of ET-1 and ET receptors rather than the ET-1 system itself.
Stimulation of ET-1 receptors leads to increased activation of protein kinase C (PKC), which is associated with PKC translocation
from the cytosol to the membrane. Persistent activation of specific PKC isoforms has been proposed to contribute to diabetic
cardiomyopathy. The purpose of this study was to determine whether chronic treatment with bosentan influences the activation
of PKC isoforms in hearts from diabetic rats. Male Wistar rats were divided into four groups: control, bosentan-treated control,
diabetic, and bosentan-treated diabetic. Diabetes was induced by the intravenous injection of 60 mg/kg streptozotocin. One
week later, treatment with bosentan (100 mg/kg/day) by oral gavage was begun and continued for 10 weeks. The heart was then
removed, homogenized, separated into soluble (cytosolic) and particulate (membrane) fractions and PKC isoform content in each
fraction was determined by Western blotting. PKC α, β2, δ, ε and ζ were all detected in hearts from both control and diabetic
rats. However, no change in the levels or distribution between the soluble and particulate fractions of any of these isoforms
could be detected in chronic diabetic hearts compared to control, whether untreated or treated with bosentan. These observations
indicate that bosentan does not improve cardiac performance in STZ diabetic rats by affecting the activation of PKC isoforms. |
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Keywords: | 1bosentan 2cardiac function 3endothelin-1 (ET-1) 5protein kinase C (PKC) 4endothelin receptor blocker 6streptozotocin-induced diabetes |
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