SAT-041 Testosterone Reduces Atherosclerosis and Plaque Specific Inflammatory Markers in the ApoE-/- Mouse Model

Low serum testosterone in men is an established cardiovascular risk factor and epidemiological evidence demonstrates an association between low testosterone and with coronary events. Clinical evidence suggests that testosterone therapy (Tth) can improve key cardiovascular risk factors in men and surrogate measures of atherosclerosis, the chronic inflammatory process underlying cardiovascular disease. Atherosclerotic plaque-specific testosterone actions are not fully understood. The present study investigates the influence of testosterone on mediators of vascular inflammation and plaque burden in an in vivo model of atherosclerosis. ApoE-/- mice were either sham operated, castrated or castrated and received fortnightly intramuscular injections of physiological doses of testosterone (mixed testosterone esters, Sustanon 100) to create 3 experimental groups; normal testosterone, testosterone deficient and testosterone replaced respectively. All groups were fed a high-fat ‘Western’ diet for 16 weeks. Lipid deposition in the aortic root was assessed by Oil Red O as an indication of atherosclerotic burden. Plaque composition was assessed immunohistochemically for indicators of stability including collagen content via Masson’s trichrome, and α-smooth muscle actin (αSMA) as well as markers of inflammation including vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), endothelial-leukocyte adhesion molecule 1 (E-Selectin), and a pan monocyte/macrophage marker (MOMA2). Testosterone deficient castrated mice had significantly increased lipid accumulation in the aortic root compared to testosterone replete sham-operated littermates (48% intima-media area vs 40%, p<0.05). Tth in castrated mice reversed this effect (39%, p<0.05). Plaque stability was not altered between groups. MOMA2 staining indicated increased infiltration and localisation of monocytes/macrophages in the plaques of castrated mice compared to sham-operated (positive staining (% of plaque) 77% vs 59%, P=0.062) and Tth treatment reduced this (77% vs 63%, P=0.1). Vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) expression were reduced in castrated mice receiving Tth compared to castrated mice receiving saline (33% vs 46%, p<0.05; and 39% vs 58%, P=0.084 respectively). No significant difference in expression of E-Selectin and αSMA were observed between groups. These findings demonstrate that low testosterone increases aortic root lipid deposition and inflammatory composition in a mouse model of atherosclerosis. Increasing testosterone levels through Tth reduces plaque specific inflammatory markers and atherosclerotic burden. This indicates an anti-inflammatory mechanism by which testosterone can protect against the development and progression of atherosclerosis to reduce cardiovascular risk in men.