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Atherosclerosis and ensuing cardiovascular disease are major causes of death with insufficient treatment options. In search for pathomechanisms of atherosclerosis, we investigated the impact of the B2 bradykinin receptor,  Bdkrb2 , on atherosclerotic lesion formation, because to date it is not clear whether the B2 bradykinin receptor is atheroprotective or atherogenic. As a model of atherosclerosis, we used hypercholesterolemic  ApoE -deficient (apolipoprotein E-deficient) mice, which develop atherosclerotic lesions in the aorta with increasing age. The role of  Bdkrb2  in atherosclerosis was studied in  ApoE -deficient mice, which were either  Bdkrb2 -deficient, or had moderately increased aortic B2 bradykinin receptor protein levels induced by transgenic  BDKRB2  expression under control of the ubiquitous CMV promoter. We found that  Bdkrb2  deficiency led to a significantly decreased atherosclerotic plaque area whereas transgenic  BDKRB2  expression enhanced atherosclerotic lesion formation in the aorta of  ApoE -deficient mice at an age of 8 months. Concomitantly, the aortic content of reactive oxygen species (ROS) was higher in  BDKRB2 -expressing mice whereas  Bdkrb2  deficiency decreased aortic ROS levels of  ApoE -deficient mice. In addition, aortic nitrate as a marker of nitric oxide activity and the endothelial nitric oxide synthase (eNOS) co-factor, tetrahydrobiopterin (BH4) were reduced in  BDKRB2 -expressing  ApoE -deficient mice. The decreased aortic BH4 content could be a consequence of increased ROS generation and down-regulated aortic expression of the BH4-synthesizing enzyme,  Gch1  (GTP cyclohydrolase 1). In agreement with a causal involvement of decreased BH4 levels in the atherogenic function of  BDKRB2 , we found that treatment with the BH4 analog, sapropterin, significantly retarded atherosclerotic plaque formation in  BDKRB2 -expressing  ApoE -deficient mice. Together our data show that the B2 bradykinin receptor is atherogenic, and the atherosclerosis-promoting function of  BDKRB2  is partially caused by decreased aortic BH4 levels, which could account for eNOS uncoupling and further enhancement of ROS generation.

Increased Reactive Oxygen Species Generation Contributes to the Atherogenic Activity of the B2 Bradykinin Receptor