Abstract 9911: Hypoxia-inducible Factor-1α Knockout in Myeloid Lineage exaggerates Angiotensin II-induced Abdominal Aortic Aneurysm

Abstract

Background: Hypoxia-inducible factor-1α (Hif1α) is a transcriptional factor that regulates various genes reacting hypoxic conditions. In atherosclerotic legion, Hif1α is thought to be regulating inflammatory responses. We previously reported that myeloid specific Proryl hydroxylase domain protein2 deletion had protective effect on cardiovascular disease in animal model. The roll of Hif1α of myeloid lineage in inflammatory response is not determined. Methods and Results: Myeloid specific Hif1α knock out mice (MyHif KO) were created using Cre-lox recombination. MyHif KO mice were crossed with Apolipoprotein E knockout (ApoEKO) mice to create double knock out mice (MyHif/ApoE DKO group, n=18). ApoEKO with Hif1α flox/flox (without Cre recombinase) mice were used as control group (n=11). Two groups were fed with high fat diet (HFD) and infused with Angiotensin II (AII, 1800ng/kg/min) by osmotic mini pump for 4 weeks to promote abdominal aortic aneurysm (AAA) formation. The genotype of mice was blinded during experiment. There was no significant difference in survival rate between two groups. MyHif/ApoE DKO increased AAA formation rate (94.4% vs 81.8% in control) and aortic diameter (2.42mm±0.21mm vs 1.89±0.27mm in control). AAA classification reported by Daugherty et al was significantly exaggerated in MyHif/ApoE DKO group (2.75±0.35 vs 1.63±0.46 in control, P=0.03). Elastin degradation grade was checked by Elastica van Gieson staining. MyHif/ApoE DKO also deteriorated the elastin degradation grade (3.91±0.08 vs 3.25±0.31, P=0.01). The number of macrophages which migrated to abdominal aorta was increased in MyHif/ApoE DKO group (565±110.3/section vs 260.5±136.5/section in control, P=0.0507), whereas MyHif/ApoE DKO did not change the glucose level, blood pressure and body weight. Peritoneal macrophages from MyHif/ApoE DKO were significantly activated the migration induced by monocyte chemotactic protein-1 in dose dependent manner. Conclusion: Hif1α of myeloid lineage might have vascular protective effect via suppressing the macrophage activation in the model of AII-induced AAA in mice.