Abstract 1152: Effect of Genetic Disruption of the AT1a Receptor on the Development of Atherosclerosis - Relevance of Bone Marrow-derived Cells
Activation of the angiotensin II type 1 (AT1) receptor is involved in the multifactorial pathogenesis of atherosclerosis. Bone marrow-derived cells contribute to regenerative and inflammatory processes in the vessel wall. We investigated the relevance of AT1 receptor expression on bone marrow cells for atherogenesis in a mouse model of atherosclerosis.
Methods and Results: Apolipoprotein E-deficent (ApoE−/−) mice and homozygous ApoE-AT1a receptor double-knockout mice (ApoE−/−AT1−/− mice) were fed a high-cholesterol diet containing 1.25% cholesterol for 7 weeks. Profound atherosclerotic lesion formation in the aortic root (oil red O staining), impaired endothelium-dependent vasodilation (organ chamber experiments with isolated aortic segments), and increased vascular oxidative stress (L-012 chemiluminescence) were found in ApoE−/− mice, but were markedly reduced in ApoE−/−AT1−/− mice. To examine the relevance of AT1 receptor expression on bone marrow (BM) cells for these effects, BM transplantations with cells derived from wild-type, AT1a−/−, or ApoE−/− mice were performed by tail vein injection into lethally irradiated ApoE−/− mice. Changes of AT1a receptor expression levels in the BM after transplantation were validated by real-time RT-PCR. Four weeks after BM transplantation and reconstitution of hematopoiesis, these mice were fed a high-cholesterol diet for 7 weeks. Atherosclerotic lesion formation in the aortic root was significantly lower in ApoE−/− mice that received AT1a−/− BM than in ApoE−/− mice that received ApoE−/− BM, although this effect was not as pronounced as the reduction of atherosclerosis in whole body ApoE-AT1a receptor double-knockout mice. AT1a−/− BM transplantation had only moderate effects on endothelial function and vascular oxidative stress as compared with ApoE−/− BM transplantation. There was no significant difference between ApoE−/− mice transplanted with wild-type BM and ApoE−/− mice transplanted with ApoE−/− BM.
Conclusions: Genetic disruption of the AT1a receptor reduces development of atherosclerosis in ApoE−/− mice. Our results indicate that AT1 receptor activation on bone marrow-derived cells contributes to the atherosclerotic process.