کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2499102 1116493 2010 7 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Mechanism of subendocardial cell proliferation in the rat and relevance for understanding drug-induced valvular heart disease in humans
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم کشاورزی و بیولوژیک علوم دامی و جانورشناسی
پیش نمایش صفحه اول مقاله
Mechanism of subendocardial cell proliferation in the rat and relevance for understanding drug-induced valvular heart disease in humans
چکیده انگلیسی
A number of drugs and drug candidates, including fenfluramine and ergot derivatives, are associated with valvulopathy in humans; however, these responses are poorly predicted from animal studies. In vitro and in vivo evidence suggests that these compounds exert their pathological effect through activation of serotonin 2B receptor (5HT2BR) signaling. However, the variable effect of fenfluramine and other 5HT2BR agonists in rodents has cast doubt on the relevance of animal findings to predicting human risk. Herein, a candidate compound, RO3013, induced subendocardial cell proliferation in the mitral and tricuspid valves in rats after only 3 days of daily dosing. Additionally, there was a treatment-related increase in immunostaining of the proliferation marker Ki67, and phosphorylated Smad3 in the heart indicative of TGFβ signaling co-localized with 5HT2BR expression. To substantiate the hypothesis that RO3013-induced valvular proliferation is secondary to 5HT2BR activation, the compound was evaluated in vitro and found to bind to the human 5HT2BR with a Ki of 3.8 μM; however, it was virtually devoid of agonist activity in a functional assay in human cells. By contrast, RO3013 bound to the rat 5HT2BR with a Ki of 1.2 μM and activated the receptor with an EC50 of 0.5 μM. This agonist potency estimate is in good agreement with the free plasma concentrations of RO3013 at which valvular proliferation was observed. These results suggest that the rat may be susceptible to 5HT2BR-mediated valvular proliferation similar to humans; yet, the significant differences between binding and functional activities can be a possible explanation for the observed species-selective receptor responses.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Experimental and Toxicologic Pathology - Volume 62, Issue 6, November 2010, Pages 607-613
نویسندگان
, , , , , , , , ,