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Discovery of an Experimental Model of Unicuspid Aortic Valve.

ABSTRACT: The epithelial growth factor receptor family of tyrosine kinases modulates embryonic formation of semilunar valves. We hypothesized that mice heterozygous for a dominant loss-of-function mutation in epithelial growth factor receptor, which are EgfrVel/+ mice, would develop anomalous aortic valves, valve dysfunction, and valvular cardiomyopathy.Aortic valves from EgfrVel/+ mice and control mice were examined by light microscopy at 2.5 to 4 months of age. Additional EgfrVel/+ and control mice underwent echocardiography at 2.5, 4.5, 8, and 12 months of age, followed by histologic examination. In young mice, microscopy revealed anatomic anomalies in 79% of EgfrVel/+ aortic valves, which resembled human unicuspid aortic valves. Anomalies were not observed in control mice. At 12 months of age, histologic architecture was grossly distorted in EgfrVel/+ aortic valves. Echocardiography detected moderate or severe aortic regurgitation, or aortic stenosis was present in 38% of EgfrVel/+ mice at 2.5 months of age (N=24) and in 74% by 8 months of age. Left ventricular enlargement, hypertrophy, and reversion to a fetal myocardial gene expression program occurred in EgfrVel/+ mice with aortic valve dysfunction, but not in EgfrVel/+ mice with near-normal aortic valve function. Myocardial fibrosis was minimal or absent in all groups.A new mouse model uniquely recapitulates salient functional, structural, and histologic features of human unicuspid aortic valve disease, which are phenotypically distinct from other forms of congenital aortic valve disease. The new model may be useful for elucidating mechanisms by which congenitally anomalous aortic valves become critically dysfunctional.

SUBMITTER: Weiss RM

PROVIDER: S-EPMC6064885 | biostudies-other | 2018 Jun

REPOSITORIES: biostudies-other

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Discovery of an Experimental Model of Unicuspid Aortic Valve.

Weiss Robert M RM Chu Yi Y Brooks Robert M RM Lund Donald D DD Cheng Justine J Zimmerman Kathy A KA Kafa Melissa K MK Sistla Phanicharan P Doshi Hardik H Shao Jian Q JQ El Accaoui Ramzi N RN Otto Catherine M CM Heistad Donald D DD

Journal of the American Heart Association 20180630 13

<h4>Background</h4>The epithelial growth factor receptor family of tyrosine kinases modulates embryonic formation of semilunar valves. We hypothesized that mice heterozygous for a dominant loss-of-function mutation in epithelial growth factor receptor, which are <i>Egfr</i><sup><i>Vel/+</i></sup> mice, would develop anomalous aortic valves, valve dysfunction, and valvular cardiomyopathy.<h4>Methods and results</h4>Aortic valves from <i>Egfr</i><sup><i>Vel/+</i></sup> mice and control mice were e ...[more]

PMID: 29960994

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Project description:Introduction: Renal failure is associated with aortic valve calcification. Using our rat model of uraemia-induced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in aortic valve calcification. We also explored the effects of raloxifene - an estrogen receptor modulator on valvular calcification. Methods: Gene array analysis was performed in aortic valves obtained from 3 groups of rats (n=7 each): calcified valves from rats fed with uremic diet -high-adenine (0.75%), high-phosphate diet (1.5%), valves after calcification resolution following diet cessation (reversibility) and control. In addition, four groups of rats (n=10 each) were used in order to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet which also received daily raloxifene. Evaluation of these groups included imaging, histology and antigen expression analysis. Results: Gene array results showed that the majority of the expressed genes that were altered were from the diet group valves. Most apoptosis-related genes were changed in a pro-apoptotic direction in calcified valves. Apoptosis and decrease in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of these ant-apoptotic pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. Conclusion: Downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure. Introduction: Renal failure is associated with aortic valve calcification. Using our rat model of uraemia-induced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in aortic valve calcification. We also explored the effects of raloxifene - an estrogen receptor modulator on valvular calcification. Methods: Gene array analysis was performed in aortic valves obtained from 3 groups of rats (n=7 each): calcified valves from rats fed with uremic diet -high-adenine (0.75%), high-phosphate diet (1.5%), valves after calcification resolution following diet cessation (reversibility) and control. In addition, four groups of rats (n=10 each) were used in order to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet which also received daily raloxifene. Evaluation of these groups included imaging, histology and antigen expression analysis. Results: Gene array results showed that the majority of the expressed genes that were altered were from the diet group valves. Most apoptosis-related genes were changed in a pro-apoptotic direction in calcified valves. Apoptosis and decrease in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of these ant-apoptotic pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. Conclusion: Downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure.

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Discovery of an Experimental Model of Unicuspid Aortic Valve.

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Discovery of an Experimental Model of Unicuspid Aortic Valve.

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