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, 23-28weeks 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.