title: Paradoxical protection from atherosclerosis and thrombosis in a mouse model of sickle cell disease.
abstract: Sickle cell disease (SCD) is associated with vascular complications including premature stroke. The role of atherothrombosis in these vascular complications is unclear. To determine the effect of SCD on atherosclerosis and thrombosis, mice with SCD along with controls were generated by transplantation of bone marrow from mice carrying the homozygous sickle cell mutation (Hbb(hβs/hβs) ) or wild-type mice (Hbb(+/+) ) into C57BL6/J or apolipoprotein E deficient (Apoe(-/-) ) recipient mice. At the time of sacrifice, 23-28 weeks following bone marrow transplantation, anaemia, reticulocytosis, and splenomegaly were present in mice receiving Hbb(hβs/hβs) bone marrow compared with control mice. Analysis of atherosclerosis involving the aortic root revealed reduced atherosclerotic lesion area with reduced macrophage content and increased collagen content in Apoe(-/-) , Hbb(hβs/hβs) mice compared to Apoe(-/-) , Hbb(+/+) mice. In a carotid thrombosis model, the time to thrombosis was prolonged in Hbb(hβs/hβs) mice compared to Hbb(+/+) mice. This apparent protective effect of SCD on atherosclerosis and thrombosis was diminished by inhibition of heme oxygenase-1 (HMOX1) using zinc protoporphyrin IX. We conclude that SCD in mice is paradoxically protective against atherosclerosis and thrombosis, highlighting the complexity of vascular events in SCD. This protective effect is at least partially mediated by induction of HMOX1.
authors.affiliation: Department of Internal Medicine, Cardiovascular Research Center, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.forename: Jintao
authors.initials: J
authors.lastname: Wang
authors.forename: Chiao
authors.initials: C
authors.lastname: Guo
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Wolffe
authors.forename: Julia
authors.initials: J
authors.lastname: Wang
authors.forename: Eddy B
authors.initials: EB
authors.lastname: Sun
authors.forename: Kori N
authors.initials: KN
authors.lastname: Bradley
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Campbell
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Eitzman
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000517:prevention & control*; D002339:Carotid Arteries / Q000473:pathology; D004195:Disease Models, Animal; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011524:Protoporphyrins / Q000494:pharmacology; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*
chemical_list: D001057:Apolipoproteins E; D008055:Lipids; D011524:Protoporphyrins; C017803:zinc protoporphyrin; D051547:Heme Oxygenase-1