O7 Toll-like receptor 3 mediates osteoblastic phenotype switch in calcific aortic valve disease

نویسندگان

چکیده

Abstract Introduction Calcific aortic valve disease (CAVD) is caused by an osteoblastic phenotype switch of valvular interstitial cells (VICs), the predominant cell type in heart valves. However, trigger for remains unknown. Toll-like receptor 3 (TLR3) part innate immune system activated viral and endogenous RNA released from injured cells. We hypothesized that mechanical strain leads to TLR3 activation leading VICs with subsequent initiation CAVD. Methods Aortic valves were obtained patients undergoing replacement or explanted hearts. isolated treated agonist poly (I: C) a TLR3/dsRNA complex inhibitor. Osteoblastic gene expression was evaluated via sequencing. Cells challenged medium analyzed alkaline phosphatase activity calcific nodule formation. Zebrafish A Flexcell used apply VICs. morphology function aged wild-type (WT) TLR3-/- mice transthoracic echocardiography, microCT histological evaluation. To confirm results second model, experiments repeated ApoE-/- ApoE-/-/TLR3-/- mice. Results showed abundant expression. Mechanical stimulation resulted activation. Stimulation lead TNF-a, IL-6, IFN-y, IL-10, Runx2 BMP2 and, towards osteoblasts as revealed sequencing enhanced production. Mice age-dependent well derived CAVD increased compared healthy control Inhibition prevention osteogenic conditioned exhibited decreased calcification after inhibition. Aged WT significantly mean gradients velocity echocardiographs. MicroCT analyses thickened leaflets commissural atherosclerotic plaques. These changes missing completely age-matched under high fat diet clear signs opening diameters leaflet thickness. these findings Conclusion VICs, whereas inhibition prevents activity. patients. show no could become effective target pharmacological

برای دانلود باید عضویت طلایی داشته باشید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Toll-Like Receptors, Inflammation, and Calcific Aortic Valve Disease

Inflammation, the primary response of innate immunity, is essential to initiate the calcification process underlying calcific aortic valve disease (CAVD), the most prevalent valvulopathy in Western countries. The pathogenesis of CAVD is multifactorial and includes inflammation, hemodynamic factors, fibrosis, and active calcification. In the development of CAVD, both innate and adaptive immune r...

متن کامل

Calcific Aortic Valve Disease

Aortic stenosis due to calcific aortic valve disease (CAVD) is currently the main indication for aortic valve replacement in developed countries (Iung et al, 2003). Due to an aging population and a decline in rheumatic heart disease, CAVD has become the most common heart valve disease in the Western countries, affecting approximately 25% of adults over 65 years, of which 2-3% has clinically sig...

متن کامل

Calcific Aortic Valve Disease

Despite the high prevalence and severe consequences of calcific aortic valve disease (CAVD), its pathogenesis remains relatively poorly understood. For many years, CAVD was considered a degenerative disease, where calcification was a consequence of normal aging. Although it is now widely accepted that CAVD is an active disease process, the erroneous degenerative label contributed to delayed pro...

متن کامل

Imaging Calcific Aortic Valve Disease

Clinical trials of medical therapy to prevent progression in calcific aortic valve disease (CAVD) are hampered by the lack of sensitive measures of disease activity in the valve leaflets. Although the long-term goal of therapy is to prevent adverse cardiovascular outcomes, including mortality and aortic valve replacement, these end points have several limitations. First, the hard end point of m...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

ژورنال

عنوان ژورنال: British Journal of Surgery

سال: 2021

ISSN: ['1365-2168', '0007-1323']

DOI: https://doi.org/10.1093/bjs/znab282.012