Published online before print October 14, 2002, doi: 10.1161/01.CIR.0000038109.84500.1E
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(Circulation. 2002;106:2503.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Inactivation of the Lysyl Oxidase Gene Lox Leads to Aortic Aneurysms, Cardiovascular Dysfunction, and Perinatal Death in Mice
From the Collagen Research Unit, Biocenter Oulu and Department of Medical Biochemistry and Molecular Biology (J.M.M., H.T., K.I.K., R. Soininen), Department of Obstetrics and Gynecology (J.R., K.M.), and Biocenter Oulu and Department of Pathology (R. Sormunen), University of Oulu, Finland.
Correspondence to Raija Soininen, PhD, Department of Medical Biochemistry and Molecular Biology, University of Oulu, PO Box 5000, 90014 Oulu, Finland. E-mail raija.soininen{at}oulu.fi
Background— The lysyl oxidases are extracellular copper enzymes that initiate the crosslinking of collagens and elastin, 5 human isoenzymes having been characterized so far. The crosslinks formed provide the tensile strength and elastic properties for various extracellular matrices, including vascular walls. We studied the role of the first described isoenzyme Lox by inactivating its gene in mice.
Methods and Results— Murine Lox gene was disrupted by routine methods. Lox-/- mice died at the end of gestation or as neonates, necropsy of the live-born pups revealing large aortic aneurysms. In light microscopy, hazy and unruffled elastic lamellae in the Lox-/- aortas were observed, and electron microscopy of the aortic walls of the Lox-/- fetuses showed highly fragmented elastic fibers and discontinuity in the smooth muscle cell layers in Lox-/- fetuses. The wall of the aorta in the Lox-/- fetuses was significantly thicker, and the diameter of the aortic lumen was significantly smaller than that in the Lox+/+ aortas. In Lox-/- fetuses, Doppler ultrasonography revealed increased impedance in the umbilical artery, descending aorta, and intracranial artery blood velocity waveforms, decreased mean velocities across cardiac inflow and outflow regions, and increased pulsatility in ductus venosus blood velocity waveforms.
Conclusions— Lox has an essential role in the development and function of the cardiovascular system. Inactivation of the Lox gene causes structural alterations in the arterial walls, leading to abnormalities in the cardiovascular functions. Alterations in LOX activity may also play a critical role in certain human cardiovascular diseases.
Key Words: aneurysm • aorta • crosslink • lysyl oxidase
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