Abstract 151: Role of Hypoxia Inducible Factor-1α in Leukocyte Recruitment to Sites of Vascular Injury and Atherosclerotic Progression 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 acute coronary syndrome (ACS) remains undefined. Since HIF-1α is a lethal knockout, we generated ApoE/SRB double null (DN) mice with HIF-1α null leukocytes using bone marrow transplantation (BMT) and hematopoietic stem cells (HSC) transducted with a lentivirus encoding a siRNA to HIF-1α or scramble.
Methods: Donor bone marrow was harvested from 6 week-old ApoE/SRB DN mice. At age 6 weeks, following lethal irradiation ApoE/SRB DN mice received 50,000 scramble or HIF-1 α: siRNA transfected HSC. Mice were weaned from probucol 2 weeks after BMT. Serial echocardiography was used to assess cardiac function. Burden of coronary atherosclerosis and macrophage recruitment were assessed.
Results: White blood cells from HIF-1 α: siRNA mice exhibited significantly less HIF-1α expression following culture in hypoxic conditions (p<0.05). HIF-1 α: siRNA mice demonstrated significantly less coronary atherosclerosis (p <0.05) and macrophage recruitment (p=0.02) in the plaque. HIF-1 α: siRNA mice showed significantly delayed time to myocardial infarction. Six weeks after cessation of probucol in the diet, control animals had an ejection fraction of 43 ± 6% compared to 73 ± 7% in HIF-1 α: siRNA mice. HIF-1 α: siRNA mice did not exhibit evidence of left ventricular dysfunction until 7.9 ± 0.4 weeks after weaning off probucol as compared to 5.3 ± 0.3 weeks in the controls. 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 (8.6 ± 0.4 vs. 6.3 ± 0.3, p<0.05).
Conclusion: Leukocyte derived HIF-1 α plays a critical role in leukocyte recruitment to the site of vascular injury and appears to be involved in the progression of coronary atherosclerosis.
- © 2012 by American Heart Association, Inc.