کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5528496 1548000 2017 18 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Dysregulation of hyaluronan homeostasis during aortic valve disease
ترجمه فارسی عنوان
اختلال در تنظیم هوموستاز هیالورونان در بیماران تحت جراحی آئورت
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
چکیده انگلیسی


- TGFβ1 alters the ratio of HA synthesizing and degrading enzymes during AVD.
- HAS and HYAL are differentially regulated by the canonical and non-canonical TGFβ pathways.
- CD44 is highly responsive to biomechanical strain.
- Pathological heavy chain hyaluronan and increased TSG6 activity are associated with AVD.

Aortic valve disease (AVD) is one of the leading causes of cardiovascular mortality. Abnormal expression of hyaluronan (HA) and its synthesizing/degrading enzymes have been observed during latent AVD however, the mechanism of impaired HA homeostasis prior to and after the onset of AVD remains unexplored. Transforming growth factor beta (TGFβ) pathway defects and biomechanical dysfunction are hallmarks of AVD, however their association with altered HA regulation is understudied. Expression of HA homeostatic markers was evaluated in diseased human aortic valves and TGFβ1-cultured porcine aortic valve tissues using histology, immunohistochemistry and Western blotting. Further, porcine valve interstitial cell cultures were stretched (using Flexcell) and simultaneously treated with exogenous TGFβ1 ± inhibitors for activated Smad2/3 (SB431542) and ERK1/2 (U0126) pathways, and differential HA regulation was assessed using qRT-PCR. Pathological heavy chain HA together with abnormal regional expression of the enzymes HAS2, HYAL1, KIAA1199, TSG6 and IαI was demonstrated in calcified valve tissues identifying the collapse of HA homeostatic machinery during human AVD. Heightened TSG6 activity likely preceded the end-stage of disease, with the existence of a transitional, pre-calcific phase characterized by HA dysregulation. TGFβ1 elicited a fibrotic remodeling response in porcine aortic valves similar to human disease pathology, with increased collagen and HYAL to HAS ratio, and site-specific abnormalities in the expression of CD44 and RHAMM receptors. Further in these porcine valves, expression of HAS2 and HYAL1 was found to be differentially regulated by the Smad2/3 and ERK1/2 pathways, and CD44 expression was highly responsive to biomechanical strain. Leveraging the regulatory pathways that control both HA maintenance in normal valves and early postnatal dysregulation of HA homeostasis during disease may identify new mechanistic insight into AVD pathogenesis.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Matrix Biology - Volume 62, October 2017, Pages 40-57
نویسندگان
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