Macrophage-specific expression of group IIA sPLA2 results in accelerated atherogenesis by increasing oxidative stress.
Group IIA secretory phospholipase A2 (sPLA2) is an acute-phase protein mediating decreased plasma HDL cholesterol and increased atherosclerosis. This study investigated the impact of macrophage-specific sPLA2 overexpression on lipoprotein metabolism and atherogenesis. Macrophages from sPLA2 transgenic mice have 2.5 times increased rates of LDL oxidation (thiobarbituric acid-reactive substances formation) in vitro (59 +/- 5 vs. 24 +/- 4 nmol malondialdehyde/mg protein; P < 0.001) dependent on functional 12/15-lipoxygenase (12/15-LO). Low density lipoprotein receptor-deficient (LDLR-/-) mice were transplanted with bone marrow from either sPLA2 transgenic mice (sPLA2--> LDLR-/-; n = 19) or wild-type C57BL/6 littermates (C57 BL/6-->LDLR-/-; n = 19) and maintained for 8 weeks on chow and then for 9 weeks on a Western-type diet. Plasma sPLA2 activity and plasma lipoprotein profiles were not significantly different between sPLA2-->LDLR-/- and C57BL/6-->LDLR-/- mice. Aortic root atherosclerosis was increased by 57% in sPLA2-->LDLR-/- mice compared with C57BL/6-->LDLR-/- controls (P < 0.05). Foam cell formation in vitro and in vivo was increased significantly. Urinary, plasma, and aortic levels of the isoprostane 8,12-iso-iPF2alpha-VI and aortic levels of 12/15-LO reaction products were each significantly higher (P < 0.001) in sPLA2-->LDLR-/- compared with C57BL/6-->LDLR-/- mice, indicating significantly increased in vivo oxidative stress in sPLA2--> LDLR-/-. These data demonstrate that macrophage-specific overexpression of human sPLA2 increases atherogenesis by directly modulating foam cell formation and in vivo oxidative stress without any effect on systemic sPLA2 activity and lipoprotein metabolism.
Tietge
Uwe J F
UJ
Department of Medicine, Charité Campus Mitte, Humboldt University, Berlin, Germany. u_tietge@yahoo.com
Pratico
Domenico
D
Ding
Tao
T
Funk
Colin D
CD
Hildebrand
Reeni B
RB
Van Berkel
Theo
T
Van Eck
Miranda
M
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism; D016026:Bone Marrow Transplantation; D005487:Foam Cells / Q000473:pathology; D054501:Group II Phospholipases A2; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D008264:Macrophages / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000235:genetics*; D010741:Phospholipases A / Q000235:genetics* / Q000378:metabolism; D054467:Phospholipases A2; D011973:Receptors, LDL / Q000235:genetics
D008074:Lipoproteins; D011973:Receptors, LDL; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2