کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8475198 | 1550445 | 2013 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Insufficient versican cleavage and Smad2 phosphorylation results in bicuspid aortic and pulmonary valves
ترجمه فارسی عنوان
شکاف ورایکونیک و فسفوریلاسیون اسامد ناشی از سوپاپ های آئورت و ریه است
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کلمات کلیدی
ECMVersicanbicuspidαSMAADAMTS5ADAMTSBAVOFTVICbpV - bpvalpha smooth muscle actin - آلفا آکتیو عضله صافepithelial to mesenchymal transition - اپیتلیال به انتقال مزانشیمالEMT - تکنسین فوریتهای پزشکیAortic valve - دریچه آئورتBicuspid aortic valve - دریچه آئورت دولتیpulmonary valve - دریچه ریویcardiac valves - دریچه های قلبValvular interstitial cells - سلول های داخل سلولی ValvularExtracellular matrix - ماتریکس خارج سلولیOutflow tract - مسیر خروجیwild type - نوع وحشیEndocardial cushions - کوسن های آندوکاردی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
بیولوژی سلول
چکیده انگلیسی
Bicuspid or bifoliate aortic valve (BAV) results in two rather than three cusps and occurs in 1-2% of the population placing them at higher risk of developing progressive aortic valve disease. Only NOTCH-1 has been linked to human BAV, and genetically modified mouse models of BAV are limited by low penetrance and additional malformations. Here we report that in the Adamts5â/â valves, collagen I, collagen III, and elastin were disrupted in the malformed hinge region that anchors the mature semilunar cusps and where the ADAMTS5 proteoglycan substrate versican, accumulates. ADAMTS5 deficient prevalvular mesenchyme also exhibited a reduction of α-smooth muscle actin and filamin A suggesting versican cleavage may be involved in TGFβ signaling. Subsequent evaluation showed a significant decrease of pSmad2 in regions of prevalvular mesenchyme in Adamts5â/â valves. To test the hypothesis that ADAMTS5 versican cleavage is required, in part, to elicit Smad2 phosphorylation we further reduced Smad2 in Adamts5â/â mice through intergenetic cross. The Adamts5â/â;Smad2+/â mice had highly penetrant BAV and bicuspid pulmonary valve (BPV) malformations as well as increased cusp and hinge size compared to the Adamts5â/â and control littermates. These studies demonstrate that semilunar cusp malformations (BAV and BPV) can arise from a failure to remodel the proteoglycan-rich provisional ECM. Specifically, faulty versican clearance due to ADAMTS5 deficiency blocks the initiation of pSmad2 signaling, which is required for excavation of endocardial cushions during aortic and pulmonary valve development. Further studies using the Adamts5â/â; Smad2+/â mice with highly penetrant and isolated BAV, may lead to new pharmacological treatments for valve disease.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular and Cellular Cardiology - Volume 60, July 2013, Pages 50-59
Journal: Journal of Molecular and Cellular Cardiology - Volume 60, July 2013, Pages 50-59
نویسندگان
Loren E. Dupuis, Hanna Osinska, Michael B. Weinstein, Robert B. Hinton, Christine B. Kern,