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Evidence for time‐dependent and adaptive mechanisms in the mitral valve following prolonged Angiotensin II infusion
Author(s) -
Thalji Nassir,
Hagler Michael,
Verzosa Grace,
Suri Rakesh,
Miller Jordan
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.764.2
Subject(s) - angiotensin ii , wnt signaling pathway , medicine , ctgf , endocrinology , biology , signal transduction , microbiology and biotechnology , growth factor , receptor
Activation of angiotensin II (AngII) signaling has been implicated in the pathogenesis of human myxomatous mitral valve prolapse (MVP). To determine whether chronic AngII infusion can elicit molecular and phenotypic manifestations of MVP, we implanted C57BL/6J mice with osmotic minipumps delivering AngII (1000ng/kg/min) or saline for 2 or 4 weeks. We probed changes in mRNA (qRT‐PCR) and protein (immunohistochemistry) levels in mitral valves, and assessed valve function by echocardiography. In line with previous findings from human MVP, 2‐week AngII infusion was associated with increased pro‐fibrotic (e.g. TGFβ2 and CTGF) and “classical” pro‐calcific (Wnt/β‐catenin) gene expression in mouse mitral valves. Increased immunofluorescence of phospho‐SMAD2 and nuclear β‐catenin suggested canonical activation of these pathways. Increased gene expression of the transcription factor Runx2 (1.8 fold‐change [FC]) and the proliferation marker KI67 (3.9 FC) were also recaptured by AngII. Surprisingly, we found that increases in Runx2 and KI67 mRNA were attenuated (both ~1.3FC) following 4 weeks of AngII, and transcriptional changes in TGFβ and Wnt/β‐catenin pathway target genes were no longer evident. The incidence of mitral regurgitation after 2 weeks of AngII (38%) did not increase when mice were treated for 4 weeks (40%). Collectively, these data suggest that there may be adaptive molecular changes occurring following prolonged AngII treatment, which oppose fibrogenic and proliferative signaling pathways. Future studies aimed at identifying key protective and deleterious molecular changes following prolonged AngII infusion will be critical to understanding mechanisms contributing to evolution of MVP.