0352: Decrease of Krox20 expression leads to aortic valve dysfunction and thickening of the valve leaflets

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• 作者：Alexis Theron ; ⁽¹⁾ ; ^{alexis.theron@ap-hm.fr" class="auth_mail" title="E-mail the corresponding author} ; Gaë ; lle Odelin⁽²⁾ ; Emilie Faure⁽²⁾ ; Jean-Franç ; ois Avierinos⁽²⁾ ; Sté ; phane Zaffran⁽²⁾
• 刊名：Archives of Cardiovascular Diseases Supplements
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：8
• 期：1
• 页码：55
• 全文大小：235 K

文摘

The mechanism involved in the onset of aortic valve (AoV) disease remains unclear.Our recent work revealed the requirement of the transcription factor Krox20 (EGR2) to regulate fibrillar collagen genes during AoV formation. Based on 50% decreased expression of KROX20/EGR2 in diseased human AoV, we examined the phenotype of the Krox20 heterozygous mice with echo and histological analyses.

Methods

Krox20^-/+ heterozygous mice (n=21) were compared to control (n=35) at different stages. Quantitative analysis of AoV histology was performed intriplicate for each genotype. We used a high-frequency echocardio-gram to evaluate the AoV function.

Results

We demonstrated that incomplete invalidation of Krox20 in mutant mice caused a significant thickening of AoV compared to control group (145±22µm vs 75±24µm, p=0.01). Within the heterozygous group, we observed that is thickening involved exclusively the AoV and worsened significantly during time (>7 month-old vs <7 month-old AoV thickening, 136±48µm vs 102±41µm, p<0001). AoV of Krox20 ^-/+ (E) 18.5 embryo were significantly more thickened than control embryo leaflet suggesting a beginning of the disease during the embryonic period.

Echo analysis showed a significant increased of AoV dysfunction in heterozygous mice vs control (52% vs 27%, p<0.001), Morphometric analysis showed that the most severe AoV dysfunction were associated with the most thickened AoV.Histological analysis in mutant mice showed an extra cellular matrix (ECM) disorganization evocative of myxomatous degeneration including excess of proteoglycan deposition and reduction of collagen fiber.Concomitant examination of Human diseased AoV showed a significant decrease in KROX20/ EGR2 expression(p<0.05). COL1A2 was down regulated in diseased Human AoV (p<0.05) as it was observed in mutant mice.

Conclusion

As previously suggested in human, we confirmed that decreased of Krox20 expression leads to degeneration of aortic leaflet, disorganization of ECM and AoV dysfunction (figure next page).