Krox20 heterozygous mice: A model of aortic regurgitation associated with decreased expression of fibrillar collagen genes

  • Théron A
  • Odelin G
  • Faure E
 et al. 
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Abstract

© 2015 Elsevier Masson SAS. Background. - The mechanism involved in the onset of aortic valve (AoV) disease remains unclear despite its poor prognosis and frequency. Recently, we reported that Krox20 (EGR2 in humans) is involved in AoV development and dysfunction. Aim. - Analyze Krox20 heterozygous mice (Krox20+/?) to discover whether incomplete expres-sion of Krox20 can cause valvular diseases. Methods. - Transcriptional levels of Col1a2/COL1A2 and Krox20/EGR2 in AoVs from Krox20+/? mice and human patients operated on for severe aortic regurgitation were evaluated byquantitative reverse transcription-polymerase chain reaction (qRT-PCR). Human control valveswere obtained from three transplanted patients without AoV disease. Twenty-one heterozy-gous Krox20+/?mice were compared with 35 controls at different ages. Three independentmeasurements of valve thickness were performed on magnified tissue sections using Image Jsoftware. In vivo valve structure and function were evaluated using the high-frequency Vevo®2100 echocardiogram.Results. - qRT-PCR analysis using AoVs from patients with severe aortic regurgitation showed adecrease in EGR2 expression associated with significant downregulation of COL1A2 expression(P < 0.05). Similar results were observed in the AoVs of Krox20+/?mice. Anatomical examinationrevealed that incomplete invalidation of Krox20 caused significant thickening of the aorticleaflet compared with controls (145 ± 22 vs. 75 ± 24 m; P = 0.01). Within the mutant group, thisthickening worsened significantly over time (Krox20+/?mice aged > 7 vs. < 7 months: 136 ± 48 vs.102 ± 41 m; P < 0.001). Moreover, the aortic leaflets of embryonic day 18.5 Krox20+/?embryoswere significantly more thickened than those from controls, suggesting that this disease beginsduring embryonic development. Echo-Doppler analysis showed a significant increase in AoVdysfunction in heterozygous versus control mice (53% vs. 17%; P < 0.001), suggesting a tightrelationship between valve architecture and function. Morphometric analysis revealed that themost severe AoV dysfunction was always associated with the most thickened valves. Classichistological analysis revealed that mutant AoVs had extracellular matrix disorganization, withfeatures of human myxomatous degeneration, including excess of proteoglycan deposition inspongiosa and reduction of collagen fibre in fibrosa, but no calcification.Conclusion. - Decreased expression of Krox20 in mice causes degeneration of the aortic leafletsand disorganization of the extracellular matrix, causing valvular dysfunction.

Author-supplied keywords

  • Aortic valve regurgitation
  • Collagens
  • Heart valve; Extracellular matrix
  • Krox20

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Authors

  • A. Théron

  • G. Odelin

  • E. Faure

  • J.-F. Avierinos

  • S. Zaffran

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