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(Circulation. 2008;117:1973-1981.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Enzymatic Activity of Lysosomal Carboxypeptidase (Cathepsin) A Is Required for Proper Elastic Fiber Formation and Inactivation of Endothelin-1

Volkan Seyrantepe, PhD; Aleksander Hinek, MD, PhD; Junzheng Peng, PhD; Michael Fedjaev, PhD; Sheila Ernest, PhD; Yoshito Kadota, PhD; Maryssa Canuel, MSc; Kohji Itoh, PhD; Carlos R. Morales, PhD; Julie Lavoie, PhD; Johanne Tremblay, PhD; Alexey V. Pshezhetsky, PhD

From the Department of Medical Genetics (V.S., M.F., S.E., A.V.P.), CHU Sainte Justine Research Center, and CHUM Research Center (J.P., J.L., J.T.), University of Montreal, Montreal, Quebec, Canada; Cardiovascular Research Program (A.H.), The Hospital for Sick Children and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Medicinal Biotechnology (Y.K., K.I.), Graduate School of Pharmaceutical Sciences, University of Tokushima, Shomachi, Japan; and Department of Anatomy and Cell Biology (M.C., C.R.M., A.V.P.), Faculty of Medicine, McGill University, Montreal, Quebec, Canada.

Correspondence to Alexey V. Pshezhetsky, PhD, Department of Medical Genetics, CHU Sainte Justine, 3175 Côte Ste-Catherine, Montreal, Quebec H3T 1C5, Canada. E-mail alexei.pchejetski{at}umontreal.ca

Received August 8, 2007; accepted February 8, 2008.

Background— Lysosomal carboxypeptidase, cathepsin A (protective protein, CathA), is a component of the lysosomal multienzyme complex along with β-galactosidase (GAL) and sialidase Neu1, where it activates Neu1 and protects GAL and Neu1 against the rapid proteolytic degradation. On the cell surface, CathA, Neu1, and the enzymatically inactive splice variant of GAL form the elastin-binding protein complex. In humans, genetic defects of CathA cause galactosialidosis, a metabolic disease characterized by combined deficiency of CathA, GAL, and Neu1 and a lysosomal storage of sialylated glycoconjugates. However, several phenotypic features of galactosialidosis patients, including hypertension and cardiomyopathies, cannot be explained by the lysosomal storage. These observations suggest that CathA may be involved in hemodynamic functions that go beyond its protective activity in the lysosome.

Methods and Results— We generated a gene-targeted mouse in which the active CathA was replaced with a mutant enzyme carrying a Ser190Ala substitution in the active site. These animals expressed physiological amounts of catalytically inactive CathA protein, capable of forming lysosomal multienzyme complex, and did not develop secondary deficiency of Neu1 and GAL. Conversely, the mice showed a reduced degradation rate of the vasoconstrictor peptide, endothelin-1, and significantly increased arterial blood pressure. CathA-deficient mice also displayed scarcity of elastic fibers in lungs, aortic adventitia, and skin.

Conclusions— Our results provide the first evidence that CathA acts in vivo as an endothelin-1–inactivating enzyme and strongly confirm a crucial role of this enzyme in effective elastic fiber formation.

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