Abstract Body: Introduction: Development of new treatments for atherosclerosis is urgent. Current treatments mainly focus on cholesterol lowering whereas other pathomechanisms such as vascular inflammation and mitochondrial dysfunction could also serve as targets.
Research Question: We asked whether targeting of mitochondrial dysfunction could alleviate atherosclerotic plaque development in mice.
Aims: Mitochondrial dysfunction in atherosclerosis was targeted by treatment with 1,2-dihydroxyanthrachinone (alizarin).
Methods: As a model of atherosclerosis, we used atherosclerosis-prone apolipoprotein E-deficient (Apoe-/-) mice. Mice were treated with alizarin (10 mg/kg/d) in drinking water for 1 month starting at an age of 9 months. Untreated Apoe-/- mice at an age of 10 months served as controls. Atherosclerotic lesion size in the aortic sinus was determined by hematoxylin-eosin staining and quantitative image analysis. Whole genome microarray gene expression profiling of aortic genes detected treatment effects on transcriptome level.
Results: Alizarin treatment significantly reduced atherosclerotic lesion size in the aortic sinus. The sinus area covered by plaques was 18.4 % ± 9.1 % in treated mice and 41.6 ± 7.1 % in untreated mice (mean ± s.d., n=5 mice per group; p=0.0020; unpaired, two-tailed t-test). Alizarin increased aortic protein levels of the translocase of the outer mitochondrial membrane 6 (TOMM6), a mechanism that could improve mitochondrial function. Concomitantly, alizarin reduced markers of atherosclerotic plaque calcification which is known to be caused by mitochondrial dysfunction and ensuing reactive oxygen species (ROS). Reduced plaque calcification and less inflammation were detected by 6.6 ± 0.1-fold reduced aortic transcript levels of the secreted phosphoprotein 1 (Spp1) in alizarin-treated mice. Alizarin also reduced proinflammatory and atherosclerosis-stimulating transcripts such as Ccr9 (C-C chemokine receptor type 9) and its ligand Ccl25 (C-C motif chemokine ligand 25). Treatment with alizarin did not alter serum cholesterol levels of Apoe-/- mice.
Conclusions: Atherosclerosis treatment with alizarin is well-tolerated, reduces plaque size, and counteracts plaque calcification and inflammation.