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(Circulation. 2005;111:629-632.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

-Galactosidase A Deficiency Accelerates Atherosclerosis in Mice With Apolipoprotein E Deficiency

Peter F. Bodary, PhD; Yuechun Shen, MD; Fernando B. Vargas, BS; Xiaoming Bi, MD; Kristen A. Ostenso, BS; Shufang Gu, MD; James A. Shayman, MD; Daniel T. Eitzman, MD

From the Department of Internal Medicine, Divisions of Cardiovascular Medicine (P.F.B., Y.S., F.B.V., X.B., K.A.O., S.G., D.T.E.) and Nephrology (J.A.S.), University of Michigan Medical Center, Ann Arbor, Mich.

Correspondence to Daniel T. Eitzman, MD, 1150 W Medical Center Dr, 7301 MSRB III, Ann Arbor, MI 48109-0644. E-mail deitzman{at}umich.edu

Received June 7, 2004; revision received October 6, 2004; accepted October 12, 2004.

Background— -Galactosidase A (Gla) deficiency leads to widespread tissue accumulation of neutral glycosphingolipids and is associated with premature vascular complications such as myocardial infarction and stroke. Glycosphingolipids have been shown to accumulate in human atherosclerotic lesions, although their role in atherogenesis is unclear.

Methods and Results— To determine whether Gla affects the progression of atherosclerosis, mice were generated with combined deficiencies of apolipoprotein E and Gla. At 45 weeks of age, Gla-deficient mice had developed more atherosclerosis than mice with normal Gla expression (25.1±14.0 versus 12.3±9.3 mm² of total lesion area, P<0.02). This increase in atherosclerosis was associated with the presence of increased Gb3, enhanced inducible nitric oxide synthase expression, and increased nitrotyrosine staining.

Conclusions— These findings suggest that deficiency of Gla leads to increased inducible nitric oxide synthase expression and accelerated atherosclerosis.

Key Words: arteriosclerosis • nitric oxide synthase • glycolipids

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