AUTHOR=Perhal Alexander , Wolf Stefan , Jamous Yahya F. , Langer Andreas , Abd Alla Joshua , Quitterer Ursula 

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

JOURNAL=Frontiers in Medicine

VOLUME=6

YEAR=2019

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2019.00032

DOI=10.3389/fmed.2019.00032

ISSN=2296-858X

ABSTRACT=<p>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, <italic>Bdkrb2</italic>, 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 <italic>ApoE</italic>-deficient (apolipoprotein E-deficient) mice, which develop atherosclerotic lesions in the aorta with increasing age. The role of <italic>Bdkrb2</italic> in atherosclerosis was studied in <italic>ApoE</italic>-deficient mice, which were either <italic>Bdkrb2</italic>-deficient, or had moderately increased aortic B2 bradykinin receptor protein levels induced by transgenic <italic>BDKRB2</italic> expression under control of the ubiquitous CMV promoter. We found that <italic>Bdkrb2</italic> deficiency led to a significantly decreased atherosclerotic plaque area whereas transgenic <italic>BDKRB2</italic> expression enhanced atherosclerotic lesion formation in the aorta of <italic>ApoE</italic>-deficient mice at an age of 8 months. Concomitantly, the aortic content of reactive oxygen species (ROS) was higher in <italic>BDKRB2</italic>-expressing mice whereas <italic>Bdkrb2</italic> deficiency decreased aortic ROS levels of <italic>ApoE</italic>-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 <italic>BDKRB2</italic>-expressing <italic>ApoE</italic>-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, <italic>Gch1</italic> (GTP cyclohydrolase 1). In agreement with a causal involvement of decreased BH4 levels in the atherogenic function of <italic>BDKRB2</italic>, we found that treatment with the BH4 analog, sapropterin, significantly retarded atherosclerotic plaque formation in <italic>BDKRB2</italic>-expressing <italic>ApoE</italic>-deficient mice. Together our data show that the B2 bradykinin receptor is atherogenic, and the atherosclerosis-promoting function of <italic>BDKRB2</italic> is partially caused by decreased aortic BH4 levels, which could account for eNOS uncoupling and further enhancement of ROS generation.</p>