Abstract 1145: An Essential Role of Angiotensin II Type 1 Receptor in the Recipient Arterial Wall, Not in Bone Marrow, in the Pathogenesis of Angiotensin II-Induced Atherosclerosis
[Background] Angiotensin II type 1 receptor (AT1R) is expressed on multiple cell types in atherosclerotic lesions such as bone marrow (BM)-derived cells (leukocytes, progenitor cells) and non-BM intrinsic arterial wall cells (endothelial cells, smooth muscle cells and fibroblasts), which are concerned with cardiovascular diseases. Although pivotal roles of AT1R in atherogenesis have been shown in animals and humans treated with AT1R blocker as well as in ApoE/AT1R-KO mice, relative roles of AT1R in BM versus AT1R in non-BM-derived intrinsic host cells in the pathogenesis of atherosclerosis have not been addressed. Here, we investigated the role of AT1R in BM versus non-BM intrinsic arterial cells in atherogenesis.
[Methods and Results] A bone marrow transplantation technique (BMT) was used to create ApoE-KO mice with selective AT1R deficiency in BM cells (BM-AT1R−/− group) and those with selective AT1R deficiency in non-BM host cells (host AT1R−/− group). As control, BMT-ApoE−/−and BMT-ApoE−/−AT1R−/− groups, in which BM were transplanted from ApoE−/− and ApoE−/−AT1R−/−mice into ApoE−/− and ApoE−/−AT1R−/− mice, respectively, were generated. Angiotensin II (Ang II) was chronically infused from 10 to 14 weeks of age. En face oil red O staining and histopathological analysis of the aorta revealed that Ang II-induced increases in atherosclerotic plaque size were evident in control BMT-ApoE−/− (1±0 % to 5±2 %) and BM-AT1R−/− mice (1±1 % to 8±3 %). In contrast, Ang II-induced atherosclerosis was blunted in host AT1R−/− mice (2±2 %, P±0.01 vs control) as well as in BMT-ApoE−/−AT1R−/− mice (2±2 %, p<0.01 vs control). Ang II infusion raised arterial pressure in BM-AT1R−/− and BMT-ApoE−/− mice, whereas no Ang II-induced increase in arterial pressure was noted in host AT1R−/− and BMT-ApoE−/−AT1R−/− mice. There was no difference in serum lipid levels among groups with or without Ang II infusion.
[Conclusion] These results demonstrate an essential role of AT1R in host arterial wall in the pathogenesis of Ang II-induced atherosclerosis. The present study provides novel insights into Ang II-induced vascular pathobiology and suggests that AT1R-mediated signals in intrinsic endothelial and smooth muscle cells may play a principal role in Ang II-induced atherogenesis.