Abstract 45: Systemic Illness in Ece1 Ablated Adult Mice
| Autor: | Jasmin Kristianto, Michael Johnson, Abigail Radcliff, Jill Koch, Timothy Hacker, Forum Patel, Ryley Zastrow, Xiaohu Wang, Baozhi Yuan, Robert Blank |
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| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | Circulation Research. 117 |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | Endothelin converting enzyme-1 (ECE1) catalyzes the conversion of inactive big endothelin 1 (ET1) to active ET1. Homozygous Ece1 knock out (KO) mice die in utero or at birth, displaying multiple abnormalities including mandibular hypoplasia and cardiac outflow tract malformations, in spite of the presence of ample tissue ET1. However, increased ECE1 activity and circulating and/or tissue ET1 are associated with many adult cardiovascular diseases, including idiopathic pulmonary fibrosis (IPF), a chronic and fatal lung disease. There is an apparent paradox between the need for ET1 in development and its harmful effects in adult disease. Therefore, our lab developed a conditional Ece1 KO mouse, in which Ece1 is ablated following tamoxifen (tam) treatment. We hypothesized that ECE1 serves to localize ET1 signals to specific cell populations and is essential in normal adult physiology. We studied the following groups: mice given vehicle rather than tam, mice lacking tam-inducible Cre recombinase, mice harboring a normal Ece1 allele ( Ece1 +/flox ), and the experimental animals (Cre Ece1 -/flox ). Mice were treated with vehicle or tam at 8-9 weeks of age. Cre Ece1 -/flox mice showed 85-100% mRNA knock-down efficiency 8 weeks after tam treatment. By 17 weeks of age, Cre Ece1 -/flox mice have tachypnea, decreased activity, and weight loss, requiring euthanasia for humane considerations. They display depleted adipose tissue mass compared to controls. By two weeks after treatment, Cre Ece1 -/flox mice had lower blood pressure relative to controls, which persisted until euthanasia at 17-20 weeks old (p=0.004). Between 17-20 weeks of age, most of Cre Ece1 -/flox mice develop pectus excavatum, enlarged right hearts and have reduced stroke volume and cardiac output as analyzed by echocardiography. Histological examination revealed eosinophilic crystalline pneumonia and increased collagen in the lung and heart. These findings are consistent with development of IPF in the experimental mice. Our findings show that Ece1 ablation in post-natal animal results in a severe cardiorespiratory disease, suggesting that ectopic activation of ET1 by other tissue proteases is the primary mechanism underlying the association of increased ET1 signaling in disease states. |
| Databáze: | OpenAIRE |
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