Abstract 1013: Deletion of Angiotensin II Type I Receptor in Bone Marrow Reduced Atherosclerotic Lesion Formation in ApoE Deficient Mice
Background; It was suggested that angiotensin II (Ang-II)-Ang-II type 1 receptor (AT1R) pathway play a pivotal role in the pathogenesis of atherosclerosis. Recently, bone marrow (BM) cells including hematopoietic stem cells were reported to express AT1R, which promotes their differentiation and proliferation. There is increasing body of evidence that BM-derived vascular progenitor cells contribute to atherosclerotic lesion formation. Here, we investigated the role of local AT1R in BM in the pathogenesis of atherosclerosis.
Methods and Results; We established ApoE−/−AT1R−/− mice, which developed less atherosclerotic lesion formation than ApoE−/−AT1R+/+ mice. We administered 10 mg/kg/day telmisartan, AT1R blocker, or 30 mg/kg/day hydralazine to 6-week-old male ApoE−/−AT1aR+/+ mice fed on western-type diet every day by gavage. At 26 weeks, systolic blood pressure and plasma total cholesterol levels were similar between the two groups. En face Sudan IV staining of aortic arch revealed significant suppression of atherosclerotic lesion area in the telmisartan group (10.8±1.6 vs. 25.1±3.9%, P=0.01). Either Ang-II (5mg/kg/day) or vehicle was infused into 20-week-old male ApoE−/−AT1R+/+ mice or ApoE−/−AT1R−/− mice for 14 days using osmotic mini-pump. En face Sudan IV staining of aortic arch revealed that Ang-II accelerated lesion progression in ApoE−/−AT1R+/+ mice (46.5±6.1 vs.13.5±2.9 %, p<0.01), but not in ApoE−/−AT1R−/− mice (5.2±1.9 vs.10.4±2.5%, NS). When the BM of ApoE−/−AT1R+/+ mice was replaced with that of ApoE−/−AT1R−/− mice, Ang-II induced acceleration of atherosclerotic lesion formation was not observed (4.8±0.8 vs. 2.5±0.3%, p=NS). On the other hand, ApoE−/−AT1R+/+ mice whose BM was replaced with that of ApoE−/−AT1R+/+ mice showed significant acceleration of atherosclerotic lesion formation by Ang-II infusion (10.2±1.8 vs. 2.6±0.6%, p<0.01).
Conclusions; Our findings suggest that AT1R in BM may play an important role in the pathogenesis of atherosclerosis in aorta.