Reduced EGFR causes abnormal valvular differentiation leading to calcific aortic stenosis and left ventricular hypertrophy in C57BL/6J but not 129S1/SvImJ mice
Reduced EGFR causes abnormal valvular differentiation leading to calcific aortic stenosis and left ventricular hypertrophy in C57BL/6J but not 129S1/SvImJ mice
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DOI：
10.1152/ajpheart.00866.2008
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发表时间：
2009-07-01
影响因子：
4.8
通讯作者：
Threadgill, David W.
中科院分区：
文献类型：
--
作者：
Barrick, Cordelia J.;Roberts, Reade B.;Threadgill, David W.
Barrick CJ, Roberts RB, Rojas M, Rajamannan NM, Suitt CB， O'Brien KD, Smyth SS, Threadgill DW。EGFR降低导致C57BL/6J小鼠瓣膜分化异常，导致钙化性主动脉狭窄和左心室肥厚，而129S1/SvImJ小鼠则没有。[J] .中华心脏杂志，2009,31(4):557 - 557。2009年5月15日首次出版；doi: 10.1152 / ajpheart.00866.2008。-表皮生长因子受体（EGFR）信号传导有助于小鼠主动脉瓣发育。由于Egfr缺失小鼠的发育表型依赖于遗传背景，因此在C57BL/6J （B6）和129S1/SvImJ（129）背景下，将次胚性Egfr（wa2）等位基因作为基因，用于鉴定Egfr相关主动脉瓣异常的潜在细胞原因。两种遗传背景的Egfr（wa2/wa2）小鼠均发生主动脉瓣增生。许多B6-Egfr（wa2/wa2）小鼠在断奶前死亡，存活到3个月或更大的小鼠出现严重的左心室肥厚和心力衰竭。与杂合对照和年龄匹配的129或B6129F1背景下的Egfr（wa2）纯合小鼠相比，B6-Egfr（wa2/wa2）小鼠的心脏表型明显伴随着更厚的主动脉瓣尖和更大的跨瓣梯度。组织学分析显示，B6-Egfr（wa2/wa2）主动脉瓣在压力梯度升高和心力衰竭进展下发生细胞变化，包括细胞增殖增加、软骨异位形成、广泛钙化和炎症浸润，类似于人类钙化性主动脉狭窄的变化。尽管有先天性瓣膜增大，129和B6129F1-Egfr（wa2/wa2）小鼠的寿命正常，没有左心室肥厚，收缩功能正常。这些结果表明EGFR活性对正常瓣膜形成的要求，并表明显性基因修饰因子抑制先天性畸形瓣膜的病理改变。这些研究为主动脉硬化和狭窄提供了一种新的模型，并提示长期抑制EGFR信号用于癌症治疗可能对易感个体的主动脉瓣产生意想不到的后果。
Barrick CJ, Roberts RB, Rojas M, Rajamannan NM, Suitt CB, O'Brien KD, Smyth SS, Threadgill DW. Reduced EGFR causes abnormal valvular differentiation leading to calcific aortic stenosis and left ventricular hypertrophy in C57BL/6J but not 129S1/SvImJ mice. Am J Physiol Heart Circ Physiol 297: H65-H75, 2009. First published May 15, 2009; doi:10.1152/ajpheart.00866.2008.-Epidermal growth factor receptor (EGFR) signaling contributes to aortic valve development in mice. Because developmental phenotypes in Egfr-null mice are dependent on genetic background, the hypomorphic Egfr(wa2) allele was made congenic on C57BL/6J (B6) and 129S1/SvImJ (129) backgrounds and used to identify the underlying cellular cause of EGFR-related aortic valve abnormalities. Egfr(wa2/wa2) mice on both genetic backgrounds develop aortic valve hyperplasia. Many B6-Egfr(wa2/wa2) mice die before weaning, and those surviving to 3 mo of age or older develop severe left ventricular hypertrophy and heart failure. The cardiac phenotype was accompanied by significantly thicker aortic cusps and larger transvalvular gradients in B6-Egfr(wa2/wa2) mice compared with heterozygous controls and age-matched Egfr(wa2) homozygous mice on either 129 or B6129F1 backgrounds. Histological analysis revealed cellular changes in B6-Egfr(wa2/wa2) aortic valves underlying elevated pressure gradients and progression to heart failure, including increased cellular proliferation, ectopic cartilage formation, extensive calcification, and inflammatory infiltrate, mimicking changes seen in human calcific aortic stenosis. Despite having congenitally enlarged valves, 129 and B6129F1-Egfr(wa2/wa2) mice have normal lifespans, absence of left ventricular hypertrophy, and normal systolic function. These results show the requirement of EGFR activity for normal valvulogenesis and demonstrate that dominantly acting genetic modifiers curtail pathological changes in congenitally deformed valves. These studies provide a novel model of aortic sclerosis and stenosis and suggest that long-term inhibition of EGFR signaling for cancer therapy may have unexpected consequences on aortic valves in susceptible individuals.