Loss of Endothelial Furin Leads to Cardiac Malformation and Early Postnatal Death
WooJin Kim,a
Rachid Essalmani,a
Dorota Szumska,b
John W. M. Creemers,c
Anton J. M. Roebroek,d
Pedro D'Orleans-Juste,e
Shoumo Bhattacharya,b
Nabil G. Seidah,a, and
Annik Prata
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada,a
Department of Cardiovascular Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom,b
Laboratory of Biochemical Neuroendocrinology,c
Laboratory for Experimental Mouse Genetics, Center for Human Genetics, K. U. Leuven, Leuven, Belgium,d
Institute of Pharmacology of Sherbrooke, University of Sherbrooke, Sherbrooke, Quebec, Canada,e
Received for publication 22 September 2011.
Revision received 19 December 2011.
Accepted for publication 14 June 2012.
Abstract:
In mammals, seven proprotein convertases (PCs) cleave secretory proteins after basic residues, and four of them are called furin-like PCs: furin, PC5, PACE4, and PC7. In vitro, they share many substrates. However, furin is essential during development since deficient embryos die at embryonic day 11 and exhibit multiple developmental defects, particularly defects related to the function of endothelial cells. To define the role of furin in endothelial cells, an endothelial cell-specific knockout (ecKO) of the Furin gene was generated. Newborns die shortly after birth, indicating that furin is essential in these cells. Magnetic resonance imaging revealed that ecKO embryos exhibit ventricular septal defects (VSD) and/or valve malformations. In addition, primary cultures of wild-type and ecKO lung endothelial cells revealed that ecKO cells are unable to grow. Growth was efficiently rescued by extracellular soluble furin. Analysis of the processing of precursors of endothelin-1 (ET-1), adrenomedullin (Adm), transforming growth factor β1 (TGF-β1), and bone morphogenetic protein 4 (BMP4) confirmed that ET-1, Adm, and TGF-β1 are in vivo substrates of endothelial furin. Mature ET-1 and BMP4 forms were reduced by 
90% in ecKO purified endothelial cells from lungs.
Address correspondence Annik Prat, prata{at}ircm.qc.ca.
Published ahead of print 25 June 2012
