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Disruption of ECE-1 and ECE-2 reveals a role for endothelin-converting enzyme-2 in murine cardiac development
Hiromi Yanagisawa, … , David E. Clouthier, Masashi Yanagisawa
Hiromi Yanagisawa, … , David E. Clouthier, Masashi Yanagisawa
Published May 15, 2000
Citation Information: J Clin Invest. 2000;105(10):1373-1382. https://doi.org/10.1172/JCI7447.
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Article

Disruption of ECE-1 and ECE-2 reveals a role for endothelin-converting enzyme-2 in murine cardiac development

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Abstract

Endothelin-converting enzyme-1 and -2 (ECE-1 and -2) are membrane-bound metalloproteases that can cleave biologically the inactive endothelin-1 (ET-1) precursor to form active ET-1 in vitro. We previously reported developmental defects in specific subsets of neural crest–derived tissues, including branchial arch–derived craniofacial structures, aortic arch arteries, and the cardiac outflow tract in ECE-1 knockout mice. To examine the role of ECE-2 in cardiovascular development, we have now generated a null mutation in ECE-2 by homologous recombination. ECE-2 null mice develop normally, are healthy into adulthood, are fertile in both sexes, and live a normal life span. However, when they are bred into an ECE-1–null background, defects in cardiac outflow structures become more severe than those in ECE-1 single knockout embryos. In addition, ECE-1–/–; ECE-2–/– double null embryos exhibited abnormal atrioventricular valve formation, a phenotype never seen in ECE-1 single knockout embryos. In the developing mouse heart, ECE-2 mRNA is expressed in the endocardial cushion mesenchyme from embyronic day (E) 12.5, in contrast to the endocardial expression of ECE-1. Levels of mature ET-1 and ET-2 in whole ECE-1–/–; ECE-2–/– embryos at E12.5 do not differ appreciably from those of ECE-1–/– embryos. The significant residual ET-1/ET-2 in the ECE-1–/–; ECE-2–/– embryos indicates that proteases distinct from ECE-1 and ECE-2 can carry out ET-1 activation in vivo.

Authors

Hiromi Yanagisawa, Robert E. Hammer, James A. Richardson, Noriaki Emoto, S. Clay Williams, Shin-ichi Takeda, David E. Clouthier, Masashi Yanagisawa

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Figure 1

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Northern blot analysis of ECE-1 mRNA (upper panel) and ECE-2 mRNA (middl...
Northern blot analysis of ECE-1 mRNA (upper panel) and ECE-2 mRNA (middle panel) in adult mouse tissues. Rehybridization with GAPDH probe is shown as an internal control for the amounts of RNA loaded (lower panel). Arrowheads show specific signals for ECE-1 and ECE-2 mRNA.

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