Published online before print August 13, 2009, doi: 10.1161/ATVBAHA.109.192963
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© 2009 American Heart Association, Inc.
Integrative Physiology/Experimental Medicine |
Lack of Tyrosylprotein Sulfotransferase Activity in Hematopoietic Cells Drastically Attenuates Atherosclerosis in Ldlr–/– Mice
From the Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (A.D.W., K.L.M.), and the Departments of Cell Biology and Medicine, University of Oklahoma Health Sciences Center (K.L.M.), Oklahoma City.
Correspondence to Andrew D. Westmuckett, PhD, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104. E-mail Andrew-Westmuckett{at}omrf.org
Objective— Leukocyte recruitment is a major contributor in the development of atherosclerosis and requires a variety of proteins such as adhesion molecules, chemokines, and chemokine receptors. Several key molecular players implicated in this process are expressed on monocytes and require protein-tyrosine sulfation for optimal function in vitro, including human CCR2, CCR5, CX3CR1, and PSGL-1. We therefore hypothesized that protein-tyrosine sulfation in hematopoietic cells plays an important role in the development of atherosclerosis.
Methods and Results— Lethally-irradiated Ldlr–/– mice were rescued with hematopoietic progenitors lacking tyrosylprotein sulfotransferase (TPST) activity attributable to deletion of the Tpst1 and Tpst2 genes. TPST deficient progenitors efficiently reconstituted hematopoiesis in Ldlr–/– recipients and transplantation had no effect on plasma lipids on a standard or atherogenic diet. However, we observed a substantial reduction in the size of atherosclerotic lesions and the number of macrophages in lesions from hyperlipidemic Ldlr–/– recipients transplanted with TPST deficient progenitors compared to wild-type progenitors. We also document for the first time that murine Psgl-1 and Cx3cr1 are tyrosine-sulfated.
Conclusions— These data demonstrate that protein-tyrosine sulfation is an important contributor to monocytes/macrophage recruitment and/or retention in a mouse model of atherosclerosis.
Leukocyte recruitment is a major contributor in the development of atherosclerosis. Several key proteins implicated in this process require tyrosine sulfation for optimal function in vitro. In this study we found that transplantation of Ldlr–/– mice with hematopoietic progenitors lacking tyrosylprotein sulfotransferase activity drastically attenuated development of atherosclerosis.
Key Words: atherosclerosis • genetically altered mice • protein-tyrosine sulfation
Related Article:
Arterioscler Thromb Vasc Biol 2009 29: 1709-1711.
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  E. Koltsova and K. Ley Tyrosine Sulfation of Leukocyte Adhesion Molecules and Chemokine Receptors Promotes Atherosclerosis Arterioscler Thromb Vasc Biol, November 1, 2009; 29(11): 1709 - 1711. [Full Text] [PDF]
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