Abstract 14683: Fibrocalcific Changes in the Aortic Valve Are Dissociated From Aortic Valve Function in EgfrWa2/Wa2 Mice
Mice homozygous for a loss-of-function mutation in the epidermal growth factor receptor (EgfrWa2/Wa2, “Wave ” mice) develop severe fibrocalcific aortic valve disease (FCAVD) and aortic regurgitation (AR) by 6 mo. of age. Heterozygous mice (Control) are normal.
Objective: To examine mechanisms of FCAVD and AR in Wave mice.
Results: At 1.5 mo. of age, 65%* of Wave mice (N = 20) had moderate/severe AR, vs. 0% of Control mice (N = 14; *p < 0.05). At 1.5 mo., proteoglycan content was increased 8-fold* in aortic valves of Wave vs. Control, but there were no increases in osteogenic markers (osterix, osteocalcin), calcification, pro-fibrotic signaling (TGF-β1, p-SMAD2), fibrosis, or apoptosis. By 6 mo. of age, osteogenic markers increased 5-fold* and calcification increased 10-fold* in aortic valves of Wave (N = 8) vs. Control (N = 7). Treatment of 1 mo. old Wave mice (N = 5) with the PPAR-γ ligand pioglitazone (Pio) for 5 mo. attenuated increases in osteogenic markers by 75% and valve calcification by 91% (p < 0.05 vs. untreated Wave mice), to levels that were not different from age-matched Control mice. Pio, however, did not reduce prevalence of moderate/severe AR (80%). At 1.5 mo. of age, LV end-diastolic volume and LV mass were increased by 102%* and 58%*, respectively, in Wave vs. Control mice. Expression of myocardial fetal genes (sk-actin*, ANP*, BNP*, β-MHC*) was increased only in Wave mice with AR, which suggests dependence on phenotype, not genotype. LVEF was normal (0.76 ± 0.06; mean ± SE) in young Wave mice, but was reduced by 12 mo. of age (0.63 ± 0.02*). Impairment of LVEF was associated with increased myocardial expression of collagens 1* and 3*. SERCA expression was normal in Wave mice at all ages.
Conclusions: Impaired EGFR signaling produces thickened proteoglycan-rich (“myxomatous”) aortic valves with aortic regurgitation, in mice. Valvular cardiomyopathy occurs prior to valve fibrosis and calcification, in Wave mice. Pio treatment significantly attenuates osteogenic signaling and aortic valve calcification in Wave mice, but does not improve valve function. The findings suggest that FCAVD in Wave mice is a response to, not the cause of, valve dysfunction, or that FCAVD and valve dysfunction are epiphenomena arising from structurally incompetent aortic valves.
- © 2013 by American Heart Association, Inc.