The Cardiovascular Institute, Tōkyō, Japan


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Publications (2)5.92 Total impact

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    ABSTRACT: Background: Since the prevalence of atrial fibrillation (AF) increases progressively with aging, especially in men, we hypothesized that testosterone might affect the occurrence of AF. Methods and Results: We examined the electrophysiological properties of the atria in isolated-perfused hearts of sham-operated male (SM), female (SF), orchiectomized male with and without administration of testosterone (ORCH-T and ORCH), and ovariectomized female (OVX) Sprague-Dawley rats. An electrophysiological study revealed that repetitive atrial responses induced by electrical stimuli significantly increased in ORCH rats without changes in other electrophysiological properties and were abolished by administration of testosterone. To investigate the underlying mechanisms, we evaluated the expression level of calcium-handling proteins. In ORCH rats, the immunoreactive protein level of ryanodine receptor type 2 (RyR2) and sodium–calcium exchanger significantly increased as compared with SM and ORCH-T rats without alterations in the level of FK506-binding protein (FKBP12.6), sarcoendoplasmic reticulum Ca-ATPase, and phospholamban. Immunoprecipitation analysis demonstrated decreased binding of FKBP12.6 to RyR2 in ORCH rats, which was prevented by testosterone. In contrast, the expression levels of these proteins showed no significant differences between SF and OVX rats. Conclusion: Deficiency of testosterone was arrhythmogenic in rat atria possibly through less binding of FKBP12.6 to RyR2, which could induce feasible calcium leakage from the sarcoendoplasmic reticulum. These results would explain, at least in part, the increase in the prevalence of AF in accordance with the decline of testosterone particularly in elderly men.
    No preview · Article · Aug 2009 · Journal of Cardiovascular Electrophysiology
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    ABSTRACT: Background: Diabetes mellitus (DM) is one of the independent risk factors for atrial fibrillation (AF). Our previous study has indicated that DM causes atrial structural remodeling with intraatrial conduction disturbances. We tested the hypothesis that the advanced glycation end products (AGEs) and the receptor for AGE (RAGE), which have been implicated in diabetic complications, are responsible for the atrial structural remodeling.Methods and Results: Diabetes was induced by streptozotocin (65 mg/kg i.p.) in 8-week-old female Sprague–Dawley rats. When 24 weeks old, their atria were subjected to histology, Western blotting, and immunohistochemistry. The HbA1c value of induced-DM rats was significantly higher than that of control rats. Histological and immunohistochemical examinations revealed that the atria of diabetic rats showed remarkable structural changes characterized by diffuse interstitial fibrosis with abundant expressions of RAGE and connective tissue growth factor (CTGF), which findings were also confirmed by Western blotting analysis. This diabetes-induced atrial fibrosis was remarkably prevented by administration of an inhibitor of AGEs formation, OPB-9195, along with reduction of CTGF expression.Conclusions: DM promoted atrial structural remodeling via the activation of the AGEs-RAGE system with upregulating CTGF. The inhibition of AGEs formation could be a novel upstream therapeutic approach for diabetes-related atrial fibrosis.
    No preview · Article · Mar 2008 · Journal of Cardiovascular Electrophysiology