Lack of tyrosylprotein sulfotransferase activity in hematopoietic cells drastically attenuates atherosclerosis in Ldlr-/- mice.
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.


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.
Westmuckett
Andrew D
AD
Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. Andrew-Westmuckett@omrf.org
Moore
Kevin L
KL
D000704:Analysis of Variance; D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006412:Hematopoietic Stem Cells / Q000201:enzymology*; D006949:Hyperlipidemias / Q000201:enzymology*; D007958:Leukocyte Count; D051379:Mice; D018345:Mice, Knockout; D011336:Probability; D011897:Random Allocation; D019707:Receptors, Chemokine / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D015238:Sulfotransferases / Q000378:metabolism*
D019707:Receptors, Chemokine; D011973:Receptors, LDL; D015238:Sulfotransferases; C039079:protein-tyrosine sulfotransferase
J Clin Invest. 2003 Feb;111(3):333-40
12569158
Nat Rev Immunol. 2008 Oct;8(10):802-15
18825131
Gen Comp Endocrinol. 2008 Mar 1;156(1):145-53
18243191
Cell. 1999 Mar 5;96(5):667-76
10089882
Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2896-901
9501187
J Leukoc Biol. 2007 Aug;82(2):226-36
17329566
Biochemistry. 1994 Jun 7;33(22):6952-9
8204629
N Engl J Med. 1999 Jan 14;340(2):115-26
9887164
Atherosclerosis. 1999 Mar;143(1):205-11
10208497
Arterioscler Thromb Vasc Biol. 2007 Feb;27(2):373-9
17138939
J Biol Chem. 2003 Jul 4;278(27):24243-6
12730193
Nature. 2002 Dec 19-26;420(6917):868-74
12490960
J Biol Chem. 2006 Apr 7;281(14):9423-31
16469738
J Biol Chem. 1995 Sep 29;270(39):22677-80
7559387
J Biol Chem. 1995 Apr 21;270(16):9571-8
7721887
J Biol Chem. 1998 Sep 18;273(38):24770-4
9733778
Methods Enzymol. 2009;461:147-70
19480918
J Immunol. 2000 Nov 1;165(9):5295-303
11046064
Circulation. 2003 Feb 25;107(7):1009-16
12600915
Chem Biol. 2000 Mar;7(3):R57-61
10712936
Atherosclerosis. 1987 Dec;68(3):231-40
3426656
Nature. 1998 Aug 27;394(6696):894-7
9732872
Arterioscler Thromb Vasc Biol. 2007 Nov;27(11):2292-301
17673705
J Biol Chem. 1991 Jan 15;266(2):740-6
1898735
Arterioscler Thromb Vasc Biol. 2003 Mar 1;23(3):447-53
12615695
Circulation. 2008 Jun 24;117(25):3227-37
18519846
J Biol Chem. 2006 Dec 8;281(49):37877-87
17046811
Biochemistry. 1992 Apr 7;31(13):3315-25
1554716
J Biol Chem. 2009 Jan 30;284(5):3096-3105
19047058
J Biol Chem. 2002 Jun 28;277(26):23781-7
11964405
J Biol Chem. 2002 May 31;277(22):19418-23
11909868