Regular Exercise Training Prevents Aortic Valve Disease in Low-Density Lipoprotein-Receptor-Deficient Mice

Background-Regular exercise training (ET) slows the progression of atherosclerotic lesions, reduces oxidative stress, and increases nitric oxide bioavailability, all of which may be expected to improve degenerative aortic valve disease. Methods and Results-Four-week-old low-density lipoprotein-receptor-deficient mice (n=94) were randomly divided into 4 groups: Group 1 (control group), normal diet plus sedentary activity; group 2 (cholesterol group), cholesterol diet plus sedentary activity; group 3 (regular ET group), cholesterol diet plus regular ET (60 min/day, 5 days/week) for 16 weeks; and group 4 (occasional exercise group), cholesterol diet plus occasional ET (1 day/week) for 16 weeks. At 20 weeks of age, histological analysis was performed. A significant increase in aortic valve thickness was evident in the cholesterol group compared with the control group. Importantly, regular but not occasional ET significantly reduced aortic valve thickness compared with the cholesterol group (control 31.3+/-3.0 mu m, cholesterol 50.1+/-3.4 mu m, regular exercise 30.4+/-1.2 mu m, and occasional exercise 48.9+/-3.2 mu m). Immunohistochemistry revealed that a cholesterol diet disrupted and regular ET preserved endothelial integrity on the aortic valve surface. Furthermore, serum myeloperoxidase, accumulation of macrophages and oxidized low-density lipoprotein, in situ superoxide, activated myofibroblasts/osteoblast phenotypes, and mineralization were increased in the cholesterol group but were decreased by regular ET. Polymerase chain reaction revealed increased messenger RNA expression for alpha-smooth muscle actin, bone morphogenetic protein-2, runt-related transcription factor-2, and alkaline phosphatase in the cholesterol group, whereas these were diminished by regular ET. Moreover, regular ET significantly increased circulating levels of fetuin-A compared with the cholesterol group. Conclusions-In the low-density lipoprotein-receptor-deficient mouse, regular ET prevents aortic valve sclerosis by numerous mechanisms, including preservation of endothelial integrity, reduction in inflammation and oxidative stress, and inhibition of the osteogenic pathway. (Circulation. 2010; 121: 759-767.)