Abstract 17449: Angiotensin II Induces Wnt/β-catenin Signaling and Cellular Proliferation in Mouse Mitral Valves
Myxomatous mitral valve degeneration (MMVD) is a prominent cardiac disease characterized by cellular proliferation, matrix remodeling, and leaflet prolapse. While much emphasis has been placed on interactions between transforming growth factor (TGF)-ß and angiotensin II (AngII) in MMVD, we recently identified Wnt/ß-catenin signaling as a novel signaling cascade activated in MMVD from whole genome profiling of human MMVD tissue. Thus, in the current study, we tested the hypothesis that chronic, in vivo administration of AngII induces Wnt/β-catenin signaling in mouse mitral valves. Young (3-5 month) C57BL/6J mice were treated for 14 days with AngII (1000 ng/kg/min) or normal saline via osmotic minipumps. We used qRT-PCR to examine expression of genes related to TGFβ activation and Wnt/β-catenin signaling, and fluorescent immunohistochemistry to evaluate changes in canonical TGFβ signaling and cellular proliferation. mRNA levels of TGFß1 and TGFß2 were increased in mitral valves from AngII versus saline infused mice, alongside a 1.4- and 2.3-fold increase in MMP2 and CTGF expression, respectively (all p<0.05). Increased phospho-Smad2 staining in AngII treated mice suggested that induction of TGFß target genes occurred via canonical Smad signaling. Interestingly, AngII treatment was also associated with increases in expression of the Wnt/β-catenin target genes WISP1 (49 ± 24%) and Runx2 (72 ± 18%) (p<0.05 for both), which have been implicated in the processes of osteogenesis and cellular proliferation. While no overt calcification was evident upon removal of tissues, we did however observe substantial increases in Ki67 staining (a marker of cellular proliferation) in AngII treated mitral valves. Collectively, our findings suggest that AngII treatment in mice recaptures key molecular changes characteristic of human MMVD, and that activation of Wnt/ß-catenin signaling in MMVD may contribute to cellular proliferation rather than osteogenesis per se. Ultimately, this novel animal model represents a robust experimental platform for the elucidation of further mechanisms underlying MMVD, and for testing novel non-surgical therapies aimed at attenuating molecular changes evident in human MMVD.
- © 2013 by American Heart Association, Inc.