Abstract 508: Role of Hypoxia Inducible Factor-1 α (HIF-1α) in Plaque Rupture and Survival in ApoE−/SRB − mice
Introduction: HIF-1α is an inducible protein stabilized by hypoxia and is thought to be an important mediator of leukocyte metabolism and inflammation. The role of HIF-1α in plaque rupture and acute coronary syndrome remains undefined. Since HIF-1α is a lethal knockout, we generated ApoE/SRB double null (DN) mice with HIF-1 α null leukocytes using bone marrow transplantation (BMT) and transfection of hematopoietic stem cells (HSC) using a lentivirus encoding an siRNA to HIF-1α.
Methods: Donor bone marrow was harvested from 6 week-old ApoE/SRB DN mice. At age 6 weeks, ApoE/SRB DN mice received 50,000 control or HIF-1α: siRNA transfected HSC. Recipients were weaned off probucol 2 weeks after BMT. Serial echocardiography was used to assess cardiac function.
Results: Bone marrow derived cells from HIF-1α: siRNA mice exhibited significantly less (~85% decrease) in HIF-1α expression following culture in hypoxic conditions. Animals reconstituted demonstrated significantly diminished leukocyte recruitment to sites of injury such as Thioglycollate induced peritonitis. Consistent with decreased inflammation in the absence of HIF-1α, HIF-1α: siRNA showed evidence of significantly delayed myocardial infarction. Six weeks after cessation of probucol in the diet, control animals had an ejection fraction of 61 ± 19.8% compared to 89.3 ± 4.2% in HIF-1α: siRNA mice. HIF-1α: siRNA mice did not exhibit evidence of myocardial infarction until 8.3 ± 0.6 weeks after weaning off probucol as compared to 6.0 ± 0.0 weeks in the controls (p=0.012). Consistent with delayed onset of myocardial infarction in HIF-1α siRNA transplanted mice, the mice with decreased HIF-1α expression survived longer than control mice (p=0.039).
Conclusion: Leukocyte derived HIF-1α plays a critical role in leukocyte recruitment to the site of vascular injury and in part mediates the inflammation associated with sites of vascular injury and plaque rupture.